rs505151

chr1-55063514-G-Achr1-55063514-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 0.938

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 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	UniProt
PCSK9	NM_174936.4	c.2009G>A	p.Gly670Glu	missense_variant	12/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.2009G>A	p.Gly670Glu	missense_variant	12/12	1	NM_174936.4	P2

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

GnomAD3 exomes AF: 0.948 AC: 237334 AN: 250432 Hom.: 112846 AF XY: 0.952 AC XY: 129042 AN XY: 135556

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.: 91 AF XY: 0.960 AC XY: 698317 AN XY: 727154

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.: 35 AF XY: 0.901 AC XY: 67124 AN XY: 74464

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:18

Revision: criteria provided, multiple submitters, no conflicts

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	Iberoamerican FH Network	Mar 01, 2016	- -
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	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 -
Benign, criteria provided, single submitter	curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	-	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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. -

Familial hypercholesterolemia Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Feb 09, 2023

- -

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
MutationTaster	Benign	1.0	P
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

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: rs505151; hg19: chr1-55529187;