rs562556

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.1420G>A(p.Val474Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,611,942 control chromosomes in the GnomAD database, including 560,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V474V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.83 ( 52804 hom., cov: 31)

Exomes 𝑓: 0.83 ( 507651 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.619

Publications

134 publications found

Variant links:

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 11 uncertain in NM_174936.4

BP4

Computational evidence support a benign effect (MetaRNN=7.670029E-7).

BP6

Variant 1-55058564-G-A is Benign according to our data. Variant chr1-55058564-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 201124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1420G>A	p.Val474Ile	missense_variant	Exon 9 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1420G>A	p.Val474Ile	missense_variant	Exon 9 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.832

AC:

126474

AN:

152014

Hom.:

52772

Cov.:

show subpopulations

Gnomad AFR

AF:

0.789

Gnomad AMI

AF:

0.874

Gnomad AMR

AF:

0.883

Gnomad ASJ

AF:

0.815

Gnomad EAS

AF:

0.991

Gnomad SAS

AF:

0.888

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.831

Gnomad OTH

AF:

0.856

GnomAD2 exomes

AF:

0.857

AC:

215212

AN:

251218

AF XY:

0.854

show subpopulations

Gnomad AFR exome

AF:

0.787

Gnomad AMR exome

AF:

0.915

Gnomad ASJ exome

AF:

0.814

Gnomad EAS exome

AF:

0.993

Gnomad FIN exome

AF:

0.826

Gnomad NFE exome

AF:

0.832

Gnomad OTH exome

AF:

0.860

GnomAD4 exome

AF:

0.833

AC:

1216353

AN:

1459810

Hom.:

507651

Cov.:

AF XY:

0.834

AC XY:

605946

AN XY:

726216

show subpopulations

African (AFR)

AF:

0.790

AC:

26389

AN:

33410

American (AMR)

AF:

0.911

AC:

40737

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.813

AC:

21249

AN:

26136

East Asian (EAS)

AF:

0.978

AC:

38846

AN:

39700

South Asian (SAS)

AF:

0.874

AC:

75273

AN:

86172

European-Finnish (FIN)

AF:

0.829

AC:

44182

AN:

53314

Middle Eastern (MID)

AF:

0.873

AC:

3614

AN:

4142

European-Non Finnish (NFE)

AF:

0.824

AC:

915724

AN:

1111990

Other (OTH)

AF:

0.836

AC:

50339

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

13423

26845

40268

53690

67113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20992

41984

62976

83968

104960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.832

AC:

126561

AN:

152132

Hom.:

52804

Cov.:

AF XY:

0.834

AC XY:

61987

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.789

AC:

32734

AN:

41480

American (AMR)

AF:

0.883

AC:

13514

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.815

AC:

2828

AN:

3472

East Asian (EAS)

AF:

0.991

AC:

5109

AN:

5156

South Asian (SAS)

AF:

0.887

AC:

4288

AN:

4832

European-Finnish (FIN)

AF:

0.822

AC:

8702

AN:

10580

Middle Eastern (MID)

AF:

0.864

AC:

254

AN:

294

European-Non Finnish (NFE)

AF:

0.831

AC:

56523

AN:

67992

Other (OTH)

AF:

0.858

AC:

1812

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1097

2194

3291

4388

5485

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.832

Hom.:

242171

Bravo

AF:

0.834

TwinsUK

AF:

0.821

AC:

3045

ALSPAC

AF:

0.807

AC:

3110

ESP6500AA

AF:

0.787

AC:

3468

ESP6500EA

AF:

0.833

AC:

7168

ExAC

AF:

0.854

AC:

103723

Asia WGS

AF:

0.923

AC:

3208

AN:

3476

EpiCase

AF:

0.829

EpiControl

AF:

0.825

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hypercholesterolemia, familial, 1

Benign:4

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

MAF = 20% in 100 subjects with average plasma cholesterol -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:3

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial hypercholesterolemia

Benign:2

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 02, 2022

GENinCode PLC

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypobetalipoproteinemia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Dec 08, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.036

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.087

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.20

MetaRNN

Benign

7.7e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PhyloP100

-0.62

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.27

REVEL

Benign

0.051

Sift

Benign

0.41

Sift4G

Benign

0.19

Polyphen

0.013

Vest4

0.025

MPC

0.18

ClinPred

0.015

GERP RS

-8.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.049

gMVP

0.51

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over