rs754936553

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_174936.4(PCSK9):c.1850C>A(p.Ala617Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,597,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A617T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.535

Publications

3 publications found

Variant links:

COSMIC-nc: COSV53775244

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
homozygous familial hypercholesterolemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PCSK9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06606811).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_174936.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	NM_174936.4	MANE Select	c.1850C>A	p.Ala617Asp	missense	Exon 11 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.1973C>A	p.Ala658Asp	missense	Exon 12 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.1892C>A	p.Ala631Asp	missense	Exon 11 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1850C>A	p.Ala617Asp	missense	Exon 11 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.2207C>A	p.Ala736Asp	missense	Exon 11 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.1973C>A	p.Ala658Asp	missense	Exon 12 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000917

AC:

AN:

218130

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1445780

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33238

American (AMR)

AF:

0.00

AC:

AN:

42358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25718

East Asian (EAS)

AF:

0.00

AC:

AN:

38992

South Asian (SAS)

AF:

0.00

AC:

AN:

83196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000362

AC:

AN:

1104638

Other (OTH)

AF:

0.00

AC:

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Hypercholesterolemia, autosomal dominant, 3 (1)

Hypercholesterolemia, familial, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

5.2

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.064

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.47

M_CAP

Benign

0.024

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.34

PhyloP100

0.54

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.46

REVEL

Benign

0.12

Sift

Benign

0.089

Sift4G

Benign

0.36

Polyphen

0.0010

Vest4

0.078

MutPred

0.26

Gain of disorder (P = 0.1173)

MVP

0.48

MPC

0.34

ClinPred

0.022

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.57

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over