rs505151

Variant names:

• chr1-55063514-G-A
• rs505151
• NM_174936.4:c.2009G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-55063514-G-A
• chr1-55063514-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.2009G>A​(p.Gly670Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.954 in 1,613,984 control chromosomes in the GnomAD database, including 735,949 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62321 hom., cov: 35)
  • Exomes 𝑓: 0.96 (673628 hom.)
• Consequence: PCSK9 NM_174936.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 0.938
• Publications: 187 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2124301E-6).
• BP6: Variant 1-55063514-G-A is Benign according to our data. Variant chr1-55063514-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.2009G>A	p.Gly670Glu	missense_variant	Exon 12 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.2009G>A	p.Gly670Glu	missense_variant	Exon 12 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136902 AN: 152176 Hom.: 62302 Cov.: 35

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.946

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.946

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.961

Gnomad OTH AF: 0.928

GnomAD2 exomes AF: 0.948 AC: 237334 AN: 250432 AF XY: 0.952

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.973

Gnomad ASJ exome AF: 0.946

Gnomad EAS exome AF: 0.948

Gnomad FIN exome AF: 0.947

Gnomad NFE exome AF: 0.962

Gnomad OTH exome AF: 0.957

GnomAD4 exome AF: 0.959 AC: 1402225 AN: 1461688 Hom.: 673628 Cov.: 91 AF XY: 0.960 AC XY: 698317 AN XY: 727154

African (AFR) AF: 0.727 AC: 24343 AN: 33478

American (AMR) AF: 0.970 AC: 43386 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 24786 AN: 26130

East Asian (EAS) AF: 0.951 AC: 37739 AN: 39700

South Asian (SAS) AF: 0.976 AC: 84218 AN: 86248

European-Finnish (FIN) AF: 0.949 AC: 50632 AN: 53342

Middle Eastern (MID) AF: 0.954 AC: 5441 AN: 5706

European-Non Finnish (NFE) AF: 0.966 AC: 1074311 AN: 1111982

Other (OTH) AF: 0.950 AC: 57369 AN: 60382

GnomAD4 genome AF: 0.899 AC: 136972 AN: 152296 Hom.: 62321 Cov.: 35 AF XY: 0.901 AC XY: 67124 AN XY: 74464

African (AFR) AF: 0.743 AC: 30858 AN: 41546

American (AMR) AF: 0.958 AC: 14662 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.946 AC: 3286 AN: 3472

East Asian (EAS) AF: 0.949 AC: 4907 AN: 5172

South Asian (SAS) AF: 0.977 AC: 4723 AN: 4834

European-Finnish (FIN) AF: 0.946 AC: 10050 AN: 10624

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.961 AC: 65379 AN: 68014

Other (OTH) AF: 0.929 AC: 1966 AN: 2116

Alfa AF: 0.945 Hom.: 238122

Bravo AF: 0.893

TwinsUK AF: 0.968 AC: 3589

ALSPAC AF: 0.967 AC: 3727

ESP6500AA AF: 0.743 AC: 3272

ESP6500EA AF: 0.965 AC: 8296

ExAC AF: 0.943 AC: 114445

Asia WGS AF: 0.951 AC: 3306 AN: 3478

EpiCase AF: 0.964

EpiControl AF: 0.966

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:6

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 22, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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 = 2% in 100 subjects with average plasma cholesterol; 291 hmz(AA) + 28 htz(GA) in 319 normolipidemic individuals; 98(AA)/100 normolipidemic individuals -

Mar 01, 2016

Iberoamerican FH Network

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

Oct 07, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

- -

-

PreventionGenetics, part of Exact Sciences

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

- -

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

Jul 06, 2022

GENinCode PLC

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

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

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. -

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	0.054
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.86
DANN	Benign	0.59
DEOGEN2	Benign	0.052	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.3	N
PhyloP100		0.94
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.067
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.29
ClinPred		0.0048	T
GERP RS		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.27
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs505151; hg19: chr1-55529187; COSMIC: COSV107314306; COSMIC: COSV107314306;