1-55061549-A-C

Position:

chr1-55061549-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_174936.4(PCSK9):c.1856A>C(p.Gln619Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000735 in 1,596,476 control chromosomes in the GnomAD database, including 16 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0040 ( 9 hom., cov: 33)

Exomes 𝑓: 0.00039 ( 7 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:8

Conservation

PhyloP100: -1.27

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055326223).

BP6

Variant 1-55061549-A-C is Benign according to our data. Variant chr1-55061549-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 375852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55061549-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00404 (615/152324) while in subpopulation AFR AF= 0.0144 (599/41582). AF 95% confidence interval is 0.0135. There are 9 homozygotes in gnomad4. There are 289 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 615 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1856A>C	p.Gln619Pro	missense_variant	11/12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1856A>C	p.Gln619Pro	missense_variant	11/12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00404

AC:

615

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000961

AC:

207

AN:

215432

Hom.:

AF XY:

0.000681

AC XY:

AN XY:

116068

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.000226

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000314

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000386

AC:

558

AN:

1444152

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

222

AN XY:

716466

show subpopulations

Gnomad4 AFR exome

AF:

0.0153

Gnomad4 AMR exome

AF:

0.000381

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000634

Gnomad4 OTH exome

AF:

0.000452

GnomAD4 genome

AF:

0.00404

AC:

615

AN:

152324

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000742

Hom.:

Bravo

AF:

0.00461

ESP6500AA

AF:

0.0135

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00102

AC:

123

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	Dec 16, 2016	subject mutated among 2600 FH index cases screened = 1 / Software predictions: Benign -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The PCSK9 c.1856A>C variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Pro. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant was found in 101/54678 control chromosomes at a frequency of 0.0018472, which is about 99 times the maximal expected frequency of a pathogenic PCSK9 allele (0.0000188), suggesting this variant is benign. This variant has been found only in Africans, including African controls (101/5202 ExAC African chromosomes) and both high and low LDL African patients in the literature, at a similar allele frequency (1.5-2%). Taken together, based on the prevalence of this variant in general population, this variant was classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2021	This variant is associated with the following publications: (PMID: 16465619, 17971861) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 23, 2018	- -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1

Pathogenic, flagged submission	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -
Uncertain significance, flagged submission	research	Laboratory of Genetics and Molecular Cardiology, University of São Paulo	Mar 01, 2016	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

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, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

3.1

DANN

Benign

0.61

DEOGEN2

Benign

0.072

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.31

REVEL

Benign

0.22

Sift

Benign

0.25

Sift4G

Benign

0.32

Polyphen

0.054

Vest4

0.26

MVP

0.46

MPC

0.29

ClinPred

0.0056

GERP RS

-0.57

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.27

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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