rs505151

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.90 ( 62321 hom., cov: 35)

Exomes 𝑓: 0.96 ( 673628 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.938

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 links:

PCSK9 (HGNC:):

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 36670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55063514-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.2009G>A	p.Gly670Glu	missense_variant	12/12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.2009G>A	p.Gly670Glu	missense_variant	12/12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.900

AC:

136902

AN:

152176

Hom.:

62302

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.948

AC:

237334

AN:

250432

Hom.:

112846

AF XY:

0.952

AC XY:

129042

AN XY:

135556

show subpopulations

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 SAS exome

AF:

0.976

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.:

AF XY:

0.960

AC XY:

698317

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.727

Gnomad4 AMR exome

AF:

0.970

Gnomad4 ASJ exome

AF:

0.949

Gnomad4 EAS exome

AF:

0.951

Gnomad4 SAS exome

AF:

0.976

Gnomad4 FIN exome

AF:

0.949

Gnomad4 NFE exome

AF:

0.966

Gnomad4 OTH exome

AF:

0.950

GnomAD4 genome

AF:

0.899

AC:

136972

AN:

152296

Hom.:

62321

Cov.:

AF XY:

0.901

AC XY:

67124

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.743

Gnomad4 AMR

AF:

0.958

Gnomad4 ASJ

AF:

0.946

Gnomad4 EAS

AF:

0.949

Gnomad4 SAS

AF:

0.977

Gnomad4 FIN

AF:

0.946

Gnomad4 NFE

AF:

0.961

Gnomad4 OTH

AF:

0.929

Alfa

AF:

0.951

Hom.:

154142

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:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Benign:6

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Benign, criteria provided, single submitter	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	MAF = 2% in 100 subjects with average plasma cholesterol; 291 hmz(AA) + 28 htz(GA) in 319 normolipidemic individuals; 98(AA)/100 normolipidemic individuals -

Hypercholesterolemia, autosomal dominant, 3

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial hypercholesterolemia

Benign:2

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 06, 2022	- -

Hypobetalipoproteinemia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.86

DANN

Benign

0.59

DEOGEN2

Benign

0.052

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0000012

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.3

PrimateAI

Benign

0.32

PROVEAN

Benign

0.52

REVEL

Benign

0.067

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.052

MPC

0.29

ClinPred

0.0048

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.27

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over