rs72646509

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_174936.4(PCSK9):c.835C>A(p.Pro279Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000237 in 1,610,234 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P279L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 3.85

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009918392).

BP6

Variant 1-55056028-C-A is Benign according to our data. Variant chr1-55056028-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 375846.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}.

BS2

High AC in GnomAd4 at 175 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.835C>A	p.Pro279Thr	missense_variant	6/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.835C>A	p.Pro279Thr	missense_variant	6/12	1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00384

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:

0.00144

GnomAD3 exomes

AF:

0.000308

AC:

AN:

243220

Hom.:

AF XY:

0.000212

AC XY:

AN XY:

132360

show subpopulations

Gnomad AFR exome

AF:

0.00355

Gnomad AMR exome

AF:

0.000379

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:

0.0000460

Gnomad OTH exome

AF:

0.000337

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1457938

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

724680

show subpopulations

Gnomad4 AFR exome

AF:

0.00401

Gnomad4 AMR exome

AF:

0.000404

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:

0.0000243

Gnomad4 OTH exome

AF:

0.000366

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152296

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00387

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:

0.00142

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.00146

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, 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: Damaging -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The PCSK9 c.835C>A (p.Pro279Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 41/94810 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.004103 (31/7556). This frequency is about 205 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.00002), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature as a SNP and has been observed at equal frequencies both in patients with low LDL-C and high LDL-C. Therefore, its role in the pathophysiology of Familial Hypercholesterolemia and early onset CAD is suspect. One clinical diagnostic laboratory classified this variant as uncertain significance. Taken together, due to the relatively high frequency of the variant in the control population, this variant has been classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 03, 2023	- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2020

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 02, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.72

M_CAP

Benign

0.043

MetaRNN

Benign

0.0099

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.50

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.38

MVP

0.90

MPC

0.70

ClinPred

0.033

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.57

gMVP

0.50

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