chr1-55063542-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_174936.4(PCSK9):c.2037C>A(p.Cys679*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,613,110 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. C679C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0024 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 2 hom. )

Consequence

PCSK9
NM_174936.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4B:4O:1

Conservation

PhyloP100: 0.777

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 Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00236 (359/152360) while in subpopulation AFR AF= 0.00849 (353/41592). AF 95% confidence interval is 0.00776. There are 2 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 359 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.2037C>A	p.Cys679*	stop_gained	Exon 12 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.2037C>A	p.Cys679*	stop_gained	Exon 12 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

357

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000560

AC:

139

AN:

248284

Hom.:

AF XY:

0.000386

AC XY:

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.00805

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1460750

Hom.:

Cov.:

AF XY:

0.000195

AC XY:

142

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00921

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.000481

GnomAD4 genome

AF:

0.00236

AC:

359

AN:

152360

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00849

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.00255

ESP6500AA

AF:

0.00841

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000767

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Aug 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified at a high frequency in individuals of African ancestry and results in a significant reduction in plasma levels of LDL-C (Cohen et al., 2005; Hooper et al., 2007; Huang et al., 2009); Functional studies show that the p.(C679*) variant results in impaired PCSK9 secretion (Lakosi et al., 2009; Benjannet et al., 2012); individuals who harbor this variant have a significant reduction in plasma levels of LDL-C (Cohen et al., 2005; Hooper et al., 2007; Huang et al., 2009); Nonsense variant predicted to result in protein truncation as the last 14 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 16989838, 30227170, 24507774, 20031607, 27602404, 22875854, 30899674, 33111339, 17461796, 35056760, 34428338, 33207932, 16912035, 35546142, 35859178, 32948841, 36196022, 34340953, 33866776, 28768753, 16465619, 16554528, 18652535, 17599443, 16909389, 30726226, 33563358, 34070931, 34376796, 34606887, 34782856, 35323658, 35323699, 33647772, Pham2021, 19351729, 15654334) -

not specified

Uncertain:1Benign:1

Jul 08, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCSK9 c.2037C>A (p.Cys679X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, however the molecular mechanism of disease attributed to PCSK9 is gain-of-function. The variant allele was found at a frequency of 0.00056 in 248284 control chromosomes, predominantly at a frequency of 0.008 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 213 fold of the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Familial Hypercholesterolemia phenotype (3.8e-05). c.2037C>A has been reported in the literature in individuals affected with Hyporcholesterolemia (Cohen_2005), which may associate with other symptoms (PMID 20626336). However, this variant is likely to confer protection against coronary artery disease due to its LDLC reducing effect (PMID 24507774). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant resulted in a loss of PCSK9 secretion (Benjannet_2012). The following publications have been ascertained in the context of this evaluation (PMID: 15654334, 22875854). ClinVar contains an entry for this variant (Variation ID: 2877). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 26, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3

Uncertain:1Benign:1

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2022

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypocholesterolemia

Pathogenic:1

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

PCSK9-related disorder

Uncertain:1

Mar 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCSK9 c.2037C>A variant is predicted to result in premature protein termination (p.Cys679*). This variant is located in the terminal exon of the PCSK9 gene, predicted to truncate the final 14 amino acids, and is therefore not predicted to result in nonsense mediated decay. This variant has been observed in the heterozygous state in individuals with low LDL (Cohen et al. 2005. PubMed ID: 15654334; Lakoski et al. 2009. PubMed ID: 19351729). Functional studies found this variant results in impaired secretion and lower plasma PCSK9 levels (Benjannet et al. 2006. PubMed ID: 16912035; Lakoski et al. 2009. PubMed ID: 19351729). This variant is reported in 0.80% of alleles in individuals of African descent including 1 homozygote in gnomAD. In ClinVar, this variant has conflicting interpretations of benign, uncertain significance, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/2877/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Benign:1

Apr 06, 2024

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. -

Familial hypercholesterolemia

Benign:1

Jan 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Low density lipoprotein cholesterol level quantitative trait locus 1

Other:1

Mar 23, 2006

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.81

Vest4

0.83

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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