1-55058524-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_174936.4(PCSK9):c.1380A>G(p.Val460Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,612,026 control chromosomes in the GnomAD database, including 560,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 52811 hom., cov: 32)

Exomes 𝑓: 0.83 ( 507719 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-55058524-A-G is Benign according to our data. Variant chr1-55058524-A-G is described in ClinVar as [Benign]. Clinvar id is 201126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058524-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.5 with no splicing effect.

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.1380A>G	p.Val460Val	synonymous_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.1380A>G	p.Val460Val	synonymous_variant	Exon 9 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.832

AC:

126484

AN:

152014

Hom.:

52779

Cov.:

show subpopulations

Gnomad AFR

AF:

0.790

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

GnomAD3 exomes

AF:

0.857

AC:

215309

AN:

251326

Hom.:

92547

AF XY:

0.854

AC XY:

116064

AN XY:

135874

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 SAS exome

AF:

0.874

Gnomad FIN exome

AF:

0.827

Gnomad NFE exome

AF:

0.832

Gnomad OTH exome

AF:

0.860

GnomAD4 exome

AF:

0.833

AC:

1216466

AN:

1459894

Hom.:

507719

Cov.:

AF XY:

0.834

AC XY:

605989

AN XY:

726242

show subpopulations

Gnomad4 AFR exome

AF:

0.790

Gnomad4 AMR exome

AF:

0.911

Gnomad4 ASJ exome

AF:

0.813

Gnomad4 EAS exome

AF:

0.979

Gnomad4 SAS exome

AF:

0.874

Gnomad4 FIN exome

AF:

0.829

Gnomad4 NFE exome

AF:

0.824

Gnomad4 OTH exome

AF:

0.836

GnomAD4 genome

AF:

0.832

AC:

126571

AN:

152132

Hom.:

52811

Cov.:

AF XY:

0.834

AC XY:

61993

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.789

Gnomad4 AMR

AF:

0.883

Gnomad4 ASJ

AF:

0.815

Gnomad4 EAS

AF:

0.991

Gnomad4 SAS

AF:

0.888

Gnomad4 FIN

AF:

0.822

Gnomad4 NFE

AF:

0.831

Gnomad4 OTH

AF:

0.858

Alfa

AF:

0.830

Hom.:

66707

Bravo

AF:

0.834

Asia WGS

AF:

0.923

AC:

3209

AN:

3476

EpiCase

AF:

0.829

EpiControl

AF:

0.825

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:5

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

- -

Sep 05, 2021

Genome-Nilou Lab

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

- -

Hypercholesterolemia, familial, 1

Benign:4

Mar 01, 2016

Iberoamerican FH Network

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

- -

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:2

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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial hypercholesterolemia

Benign:2

Jul 01, 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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

BayesDel_noAF

Benign

-0.62

CADD

Benign

8.9

DANN

Benign

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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