rs146471967

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_174936.4(PCSK9):c.1171C>A(p.His391Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 1,611,392 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. H391H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 1 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 4.77

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24483848).

BP6

Variant 1-55057505-C-A is Benign according to our data. Variant chr1-55057505-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496557.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAd at 112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4 linkuse as main transcript	c.1171C>A	p.His391Asn	missense_variant	7/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5 linkuse as main transcript	c.1171C>A	p.His391Asn	missense_variant	7/12	1	NM_174936.4	P2	Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

245980

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

133138

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.0000292

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:

0.00

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000679

AC:

AN:

1459064

Hom.:

Cov.:

AF XY:

0.0000661

AC XY:

AN XY:

725660

show subpopulations

Gnomad4 AFR exome

AF:

0.00278

Gnomad4 AMR exome

AF:

0.0000225

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:

0.00

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000735

AC:

112

AN:

152328

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00267

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.000328

Hom.:

Bravo

AF:

0.000884

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000206

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 22, 2016

Variant summary: The PCSK9 c.1171C>A (p.His391Asn) variant involves the alteration of a conserved nucleotide. 3/5 in silico tools predict a damaging outcome. This variant was found in 24/92630 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0029644 (24/8096). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic PCSK9 variant (0.0000938), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Moreover, the variant was identified in pts with hypocholesterolemia, mainly of African origin. However, from a study, LDL-C lowering effect was statistically insignificant (Kotowski_2006). There are no published functional studies for this variant. Based on existing evidence, this variant is not associated with hypercholesterolemia, and there is no sufficient evidence that it can cause hypocholesterolemia. Some publications suggested that this variant is loss of function mutation without providing conclusive evidence. Taken together, the variant was classified as possibly benign variant for Hypercholesterolemia phenotype. -

Familial hypercholesterolemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.023

MetaRNN

Benign

0.24

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

5.0

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.67

Sift

Benign

0.083

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.78

MVP

0.86

MPC

0.89

ClinPred

0.24

GERP RS

3.2

Varity_R

0.96

gMVP

0.91

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