rs28362286

chr1-55063542-C-Achr1-55063542-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_174936.4(PCSK9):c.2037C>A(p.Cys679Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:3 O:1
• Conservation: PhyloP100: 0.777

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM4: Stoplost variant in NM_174936.4 Downstream stopcodon found after 788 codons.
• BS2: High AC in GnomAd at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.2037C>A	p.Cys679Ter	stop_gained	12/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.2037C>A	p.Cys679Ter	stop_gained	12/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.00234 AC: 357 AN: 152242 Hom.: 2 Cov.: 33

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.: 1 AF XY: 0.000386 AC XY: 52 AN XY: 134770

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.: 2 Cov.: 33 AF XY: 0.000195 AC XY: 142 AN XY: 726724

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.: 2 Cov.: 33 AF XY: 0.00217 AC XY: 162 AN XY: 74490

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.: 0

Bravo AF: 0.00255

ESP6500AA AF: 0.00841 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000767 AC: 93

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 02, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 11, 2022	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 22, 2021	Variant summary: PCSK9 c.2037C>A (p.Cys679X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for Hyporcholesterolemia. Truncations downstream of this position have been classified as pathogenic by our laboratory. 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 homozygotes. 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), suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. 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). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n=2, Pathogenic n=1, VUS n=1). Based on the evidence outlined above, the variant was classified as VUS. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 26, 2021	- -

Hypercholesterolemia, autosomal dominant, 3 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Mar 14, 2022	- -

Hypocholesterolemia Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

-

- -

Familial hypercholesterolemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 01, 2022

- -

Low density lipoprotein cholesterol level quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Mar 23, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.81	D
MutationTaster	Benign	1.0	D
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

Other links and lift over

dbSNP: rs28362286; hg19: chr1-55529215;