ExonSkipDB: functional annotation of exon skipping event in human

Gene summary for PCSK9

Gene summary

Gene information	Gene symbol	PCSK9
	Gene ID	255738
	Gene name	proprotein convertase subtilisin/kexin type 9
	Synonyms	FH3\|HCHOLA3\|LDLCQ1\|NARC-1\|NARC1\|PC9
	Cytomap	1p32.3
	Type of gene	protein-coding
	Description	proprotein convertase subtilisin/kexin type 9convertase subtilisin/kexin type 9 preproproteinneural apoptosis regulated convertase 1subtilisin/kexin-like protease PC9
	Modification date	20180519
	UniProtAcc	Q8NBP7
	Context	PubMed: PCSK9 [Title/Abstract] AND exon [Title/Abstract] AND skip [Title/Abstract] - Title (PMID)

Gene ontology of each this gene with evidence of Inferred from Direct Assay (IDA) from Entrez

Gene	GO ID	GO term	PubMed ID
PCSK9	GO:0001920	negative regulation of receptor recycling	17452316\|22848640
PCSK9	GO:0002092	positive regulation of receptor internalization	17328821
PCSK9	GO:0007041	lysosomal transport	17452316
PCSK9	GO:0010469	regulation of signaling receptor activity	17328821
PCSK9	GO:0010989	negative regulation of low-density lipoprotein particle clearance	17328821\|22848640
PCSK9	GO:0016540	protein autoprocessing	14622975
PCSK9	GO:0032802	low-density lipoprotein particle receptor catabolic process	16912035\|18197702
PCSK9	GO:0032805	positive regulation of low-density lipoprotein particle receptor catabolic process	22848640
PCSK9	GO:1905596	negative regulation of low-density lipoprotein particle receptor binding	22848640
PCSK9	GO:1905598	negative regulation of low-density lipoprotein receptor activity	22848640
PCSK9	GO:1905601	negative regulation of receptor-mediated endocytosis involved in cholesterol transport	22848640
PCSK9	GO:2000650	negative regulation of sodium ion transmembrane transporter activity	22493497

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Exon skipping events across known transcript of Ensembl for PCSK9 from UCSC genome browser

Skipped exons in TCGA and GTEx based on Ensembl gene isoform structure.
* Click on the image to open the UCSC genome browser with custom track showing this image in a new window.

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Gene isoform structures and expression levels for PCSK9

Expression levels of gene isoforms across TCGA.

Expression levels of gene isoforms across GTEx.

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Exon skipping events with PSIs in TCGA for PCSK9

Information of exkip skipping event in TCGA.

Exon skip ID	chr	Exons involved in exon skipping	Skipped exon	ENSG	ENSTs
exon_skip_6708	1	55505430:55505717:55509515:55509707:55512195:55512319	55509515:55509707	ENSG00000169174.9	ENST00000452118.2
exon_skip_6712	1	55509515:55509707:55512195:55512319:55517950:55518084	55512195:55512319	ENSG00000169174.9	ENST00000302118.5
exon_skip_6713	1	55512195:55512319:55516864:55517126:55517950:55518084	55516864:55517126	ENSG00000169174.9	ENST00000452118.2
exon_skip_6715	1	55517950:55518084:55518322:55518464:55521665:55521862	55518322:55518464	ENSG00000169174.9	ENST00000543384.1,ENST00000490692.1,ENST00000302118.5
exon_skip_6716	1	55523100:55523187:55523708:55523830:55524171:55524320	55523708:55523830	ENSG00000169174.9	ENST00000543384.1
exon_skip_6717	1	55523100:55523187:55523708:55523882:55524171:55524320	55523708:55523882	ENSG00000169174.9	ENST00000490692.1,ENST00000302118.5
exon_skip_6720	1	55524171:55524320:55525158:55525336:55527047:55527229	55525158:55525336	ENSG00000169174.9	ENST00000543384.1,ENST00000302118.5
exon_skip_6722	1	55525158:55525336:55527047:55527229:55529041:55529112	55527047:55527229	ENSG00000169174.9	ENST00000543384.1,ENST00000302118.5

PSI values of skipped exons in TCGA.

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Exon skipping events with PSIs in GTEx for PCSK9

Information of exkip skipping event in GTEx

Exon skip ID	chr	Exons involved in exon skipping	Skipped exon	ENSG	ENSTs
exon_skip_6708	1	55505430:55505717:55509515:55509707:55512195:55512319	55509515:55509707	ENSG00000169174.9	ENST00000452118.2
exon_skip_6712	1	55509515:55509707:55512195:55512319:55517950:55518084	55512195:55512319	ENSG00000169174.9	ENST00000302118.5
exon_skip_6713	1	55512195:55512319:55516864:55517126:55517950:55518084	55516864:55517126	ENSG00000169174.9	ENST00000452118.2
exon_skip_6715	1	55517950:55518084:55518322:55518464:55521665:55521862	55518322:55518464	ENSG00000169174.9	ENST00000302118.5,ENST00000543384.1,ENST00000490692.1
exon_skip_6716	1	55523100:55523187:55523708:55523830:55524171:55524320	55523708:55523830	ENSG00000169174.9	ENST00000543384.1
exon_skip_6717	1	55523100:55523187:55523708:55523882:55524171:55524320	55523708:55523882	ENSG00000169174.9	ENST00000302118.5,ENST00000490692.1
exon_skip_6720	1	55524171:55524320:55525158:55525336:55527047:55527229	55525158:55525336	ENSG00000169174.9	ENST00000302118.5,ENST00000543384.1
exon_skip_6722	1	55525158:55525336:55527047:55527229:55529041:55529112	55527047:55527229	ENSG00000169174.9	ENST00000302118.5,ENST00000543384.1

PSI values of skipped exons in GTEx.

* Skipped exon sequences.

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Open reading frame (ORF) annotation in the exon skipping event for PCSK9

Open reading frame (ORF) of individual exon skipping events in TCGA based on the Ensembl gene structure combined from isoforms.

ENST	Start of skipped exon	End of skipped exon	ORF
ENST00000302118	55512195	55512319	Frame-shift
ENST00000302118	55518322	55518464	Frame-shift
ENST00000302118	55525158	55525336	Frame-shift
ENST00000302118	55527047	55527229	Frame-shift
ENST00000302118	55523708	55523882	In-frame

Open reading frame (ORF) of individual exon skipping events in GTEx based on the Ensembl gene structure combined from isoforms.

ENST	Start of skipped exon	End of skipped exon	ORF
ENST00000302118	55512195	55512319	Frame-shift
ENST00000302118	55518322	55518464	Frame-shift
ENST00000302118	55525158	55525336	Frame-shift
ENST00000302118	55527047	55527229	Frame-shift
ENST00000302118	55523708	55523882	In-frame

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Infer the effects of exon skipping event on protein functional features for PCSK9

Exon skipping at the protein sequence level and followed lost functional features.
* Click on the image to enlarge it in a new window.

Loci of skipped exons in TCGA across genomic, transcript, and protein sequence levels of In-frame cases.

ENST	Length of mRNA	Length of AA seq.	Genomic start	Genomic end	mRNA start	mRNA end	AA start	AA end
ENST00000302118	3654	692	55523708	55523882	1471	1644	393	451

Loci of skipped exons in GTEx across genomic, transcript, and protein sequence levels of In-frame cases.

ENST	Length of mRNA	Length of AA seq.	Genomic start	Genomic end	mRNA start	mRNA end	AA start	AA end
ENST00000302118	3654	692	55523708	55523882	1471	1644	393	451

Lost protein functional features of individual exon skipping events in TCGA.

UniProt acc.	Start of exon skipping (AA)	End of exon skipping (AA)	Protein feature start (AA)	Protein feature end (AA)	Category of protein feature	Description of feature
Q8NBP7	393	451	366	692	Alternative sequence	ID=VSP_008846;Note=In isoform 2. Missing;Ontology_term=ECO:0000303;evidence=ECO:0000303\|PubMed:14702039;Dbxref=PMID:14702039
Q8NBP7	393	451	419	422	Beta strand	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	440	442	Beta strand	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:3P5B
Q8NBP7	393	451	153	692	Chain	ID=PRO_0000027121;Note=Proprotein convertase subtilisin/kexin type 9
Q8NBP7	393	451	182	424	Domain	Note=Peptidase S8
Q8NBP7	393	451	385	402	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	408	417	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	426	428	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	431	433	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	394	394	Natural variant	ID=VAR_067282;Note=Found in a patient associated with autosomal dominant hypercholesterolemia%3B unknown pathological significance. G->S;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:22095935;Dbxref=dbSNP:rs368257906,PMID:22095935
Q8NBP7	393	451	417	417	Natural variant	ID=VAR_025455;Note=H->Q;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:16465619;Dbxref=dbSNP:rs143275858,PMID:16465619
Q8NBP7	393	451	425	425	Natural variant	ID=VAR_021337;Note=N->S;Ontology_term=ECO:0000269,ECO:0000269;evidence=ECO:0000269\|PubMed:16465619,ECO:0000269\|Ref.4;Dbxref=dbSNP:rs28362261,PMID:16465619
Q8NBP7	393	451	443	443	Natural variant	ID=VAR_021338;Note=Polymorphism%3B associated with lower plasma levels of low-density lipoprotein cholesterol%3B more extensive cleavage by furin and PCSK5. A->T;Ontology_term=ECO:0000269,ECO:0000269;evidence=ECO:0000269\|PubMed:16465619,ECO:0000269\|Ref.4;
Q8NBP7	393	451	450	692	Region	Note=C-terminal domain
Q8NBP7	393	451	423	423	Sequence conflict	Note=V->A;Ontology_term=ECO:0000305;evidence=ECO:0000305
Q8NBP7	393	451	434	436	Turn	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX

Lost protein functional features of individual exon skipping events in GTEx.

UniProt acc.	Start of exon skipping (AA)	End of exon skipping (AA)	Protein feature start (AA)	Protein feature end (AA)	Category of protein feature	Description of feature
Q8NBP7	393	451	366	692	Alternative sequence	ID=VSP_008846;Note=In isoform 2. Missing;Ontology_term=ECO:0000303;evidence=ECO:0000303\|PubMed:14702039;Dbxref=PMID:14702039
Q8NBP7	393	451	419	422	Beta strand	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	440	442	Beta strand	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:3P5B
Q8NBP7	393	451	153	692	Chain	ID=PRO_0000027121;Note=Proprotein convertase subtilisin/kexin type 9
Q8NBP7	393	451	182	424	Domain	Note=Peptidase S8
Q8NBP7	393	451	385	402	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	408	417	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	426	428	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	431	433	Helix	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX
Q8NBP7	393	451	394	394	Natural variant	ID=VAR_067282;Note=Found in a patient associated with autosomal dominant hypercholesterolemia%3B unknown pathological significance. G->S;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:22095935;Dbxref=dbSNP:rs368257906,PMID:22095935
Q8NBP7	393	451	417	417	Natural variant	ID=VAR_025455;Note=H->Q;Ontology_term=ECO:0000269;evidence=ECO:0000269\|PubMed:16465619;Dbxref=dbSNP:rs143275858,PMID:16465619
Q8NBP7	393	451	425	425	Natural variant	ID=VAR_021337;Note=N->S;Ontology_term=ECO:0000269,ECO:0000269;evidence=ECO:0000269\|PubMed:16465619,ECO:0000269\|Ref.4;Dbxref=dbSNP:rs28362261,PMID:16465619
Q8NBP7	393	451	443	443	Natural variant	ID=VAR_021338;Note=Polymorphism%3B associated with lower plasma levels of low-density lipoprotein cholesterol%3B more extensive cleavage by furin and PCSK5. A->T;Ontology_term=ECO:0000269,ECO:0000269;evidence=ECO:0000269\|PubMed:16465619,ECO:0000269\|Ref.4;
Q8NBP7	393	451	450	692	Region	Note=C-terminal domain
Q8NBP7	393	451	423	423	Sequence conflict	Note=V->A;Ontology_term=ECO:0000305;evidence=ECO:0000305
Q8NBP7	393	451	434	436	Turn	Ontology_term=ECO:0000244;evidence=ECO:0000244\|PDB:4NMX

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SNVs in the skipped exons for PCSK9

- Lollipop plot for presenting exon skipping associated SNVs.
* Click on the image to enlarge it in a new window.

- Differential PSIs between mutated versus non-mutated samples.

- Non-synonymous mutations located in the skipped exons in TCGA.

Cancer type	Sample	ESID	Skipped exon start	Skipped exon end	Mutation start	Mutation end	Mutation type	Reference seq	Mutation seq	AAchange
HNSC	TCGA-BA-A6DJ-01	exon_skip_6708	55509516	55509707	55509581	55509582	Frame_Shift_Del	AG	-	p.SE91fs
STAD	TCGA-HU-A4GQ-01	exon_skip_6712	55512196	55512319	55512313	55512313	Frame_Shift_Del	C	-	p.Q172fs
LIHC	TCGA-DD-A3A0-01	exon_skip_6717	55523709	55523882	55523861	55523861	Frame_Shift_Del	C	-	p.L444fs
LIHC	TCGA-DD-A3A0-01	exon_skip_6717	55523709	55523882	55523861	55523861	Frame_Shift_Del	C	-	p.P446fs
LIHC	TCGA-DD-A3A0-01	exon_skip_6720	55525159	55525336	55525184	55525184	Frame_Shift_Del	G	-	p.R510fs
LIHC	TCGA-DD-A39Y-01	exon_skip_6720	55525159	55525336	55525320	55525320	Frame_Shift_Del	G	-	p.Q555fs
LIHC	TCGA-DD-AAE9-01	exon_skip_6722	55527048	55527229	55527047	55527047	Splice_Site	G	T	.

- Depth of coverage in the three exons composing exon skipping event

Depth of coverage in three exons

Mutation description

- Non-synonymous mutations located in the skipped exons in CCLE.

Sample	Skipped exon start	Skipped exon end	Mutation start	Mutation end	Mutation type	Reference seq	Mutation seq	AAchange
NCIH810_LUNG	55509516	55509707	55509556	55509556	Missense_Mutation	A	C	p.K83T
NCIH810_LUNG	55509516	55509707	55509589	55509589	Missense_Mutation	C	T	p.T94I
NCIH2286_LUNG	55509516	55509707	55509606	55509606	Missense_Mutation	G	T	p.A100S
EN_ENDOMETRIUM	55509516	55509707	55509627	55509627	Missense_Mutation	T	C	p.Y107H
SNU1040_LARGE_INTESTINE	55509516	55509707	55509645	55509645	Missense_Mutation	C	T	p.H113Y
LOUCY_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55509516	55509707	55509658	55509658	Missense_Mutation	G	A	p.G117D
MM386_SKIN	55509516	55509707	55509686	55509686	Missense_Mutation	G	A	p.M126I
HOP62_LUNG	55509516	55509707	55509686	55509686	Missense_Mutation	G	C	p.M126I
NCIH1339_LUNG	55512196	55512319	55512284	55512284	Missense_Mutation	C	A	p.P163H
RCHACV_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55512196	55512319	55512296	55512296	Missense_Mutation	G	T	p.R167L
HSC4_UPPER_AERODIGESTIVE_TRACT	55512196	55512319	55512299	55512299	Missense_Mutation	C	T	p.A168V
SNUC2A_LARGE_INTESTINE	55518323	55518464	55518383	55518383	Missense_Mutation	G	A	p.G240S
GP2D_LARGE_INTESTINE	55518323	55518464	55518420	55518420	Missense_Mutation	T	C	p.V252A
GP5D_LARGE_INTESTINE	55518323	55518464	55518420	55518420	Missense_Mutation	T	C	p.V252A
KMS27_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55518323	55518464	55518446	55518446	Missense_Mutation	G	T	p.V261F
CMK_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55518323	55518464	55518452	55518452	Missense_Mutation	G	A	p.G263S
TGBC1TKB_BILIARY_TRACT	55518323	55518464	55518452	55518452	Missense_Mutation	G	A	p.G263S
HA7RCC_KIDNEY	55523709	55523830	55523735	55523735	Missense_Mutation	G	A	p.E403K
HA7RCC_KIDNEY	55523709	55523882	55523735	55523735	Missense_Mutation	G	A	p.E403K
OCIM1_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55523709	55523830	55523759	55523759	Missense_Mutation	T	G	p.L411V
OCIM1_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55523709	55523882	55523759	55523759	Missense_Mutation	T	G	p.L411V
L33_PANCREAS	55523709	55523830	55523829	55523829	Missense_Mutation	G	A	p.R434Q
L33_PANCREAS	55523709	55523882	55523829	55523829	Missense_Mutation	G	A	p.R434Q
LB647SCLC_LUNG	55525159	55525336	55525209	55525209	Missense_Mutation	G	T	p.E518D
NCIH838_LUNG	55525159	55525336	55525219	55525219	Missense_Mutation	G	T	p.A522S
DV90_LUNG	55525159	55525336	55525330	55525330	Missense_Mutation	C	A	p.L559I
OC316_OVARY	55527048	55527229	55527111	55527111	Missense_Mutation	G	A	p.R582Q
OC314_OVARY	55527048	55527229	55527111	55527111	Missense_Mutation	G	A	p.R582Q
DND41_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55527048	55527229	55527129	55527129	Missense_Mutation	G	A	p.C588Y
MYLA_HAEMATOPOIETIC_AND_LYMPHOID_TISSUE	55527048	55527229	55527185	55527185	Missense_Mutation	G	A	p.E607K
SNU1040_LARGE_INTESTINE	55527048	55527229	55527215	55527215	Missense_Mutation	G	A	p.A617T
UMUC14_URINARY_TRACT	55512196	55512319	55512318	55512318	Splice_Site	C	T	p.P174P

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Splicing Quantitative Trait Loci (sQTL) in the exon skipping event for PCSK9

sQTL information located at the skipped exons.

Exon skip ID

Chromosome

Three exons

Skippped exon

ENST

Cancer type

SNP id

Location

DNA change (ref/var)

P-value

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Splicing Quantitative Trait Methylation (sQTM) in the skipped exon for PCSK9

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Survival analysis of Splicing Quantitative Trait Methylation (sQTM) in the skipped exon for PCSK9

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RelatedDrugs for PCSK9

Approved drugs targeting this gene.
(DrugBank Version 5.1.0 2018-04-02)

Gene	UniProtAcc	DrugBank ID	Drug name	Drug activity	Drug type	Drug status
	Q8NBP7	DB09302	Alirocumab	Proprotein convertase subtilisin/kexin type 9	biotech	approved

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RelatedDiseases for PCSK9

Diseases associated with this gene.
(DisGeNet 4.0)

Gene	Disease ID	Disease name	# pubmeds	Source
PCSK9	C1863551	HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT, 3	3	CTD_human;UNIPROT
PCSK9	C1956346	Coronary Artery Disease	2	CTD_human
PCSK9	C0020443	Hypercholesterolemia	1	CTD_human

	Gene summary
	Gene structures and expression levels
	Exon skipping events with PSIs in TCGA
	Exon skipping events with PSIs in GTEx
	Open reading frame (ORF) annotation in the exon skipping event
	Exon skipping events in the canonical protein sequence
	SNVs in the skipped exons with depth of coverage
	Splicing Quantitative Trait Loci (sQTLs) in the skipped exons
	Splicing Quantitative Trait Methylation (sQTM) in the skipped exon
	Related drugs with this gene
	Related diseases with this gene

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