dbSNP rs186669805: PCSK9:p.Val4Ile (chr1-55039847-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_174936.4(PCSK9):c.10G>A(p.Val4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,565,614 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. V4L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.316

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

hypercholesterolemia, autosomal dominant, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018925339).

BP6

Variant 1-55039847-G-A is Benign according to our data. Variant chr1-55039847-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492230.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000202 (286/1413248) while in subpopulation EAS AF = 0.00747 (281/37626). AF 95% confidence interval is 0.00675. There are 3 homozygotes in GnomAdExome4. There are 150 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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	UniProt
PCSK9	NM_174936.4	MANE Select	c.10G>A	p.Val4Ile	missense	Exon 1 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.10G>A	p.Val4Ile	missense	Exon 1 of 13	NP_001394169.1	A0AAQ5BGX4
PCSK9	NM_001407241.1		c.10G>A	p.Val4Ile	missense	Exon 1 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.10G>A	p.Val4Ile	missense	Exon 1 of 12	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1		c.367G>A	p.Val123Ile	missense	Exon 1 of 12	ENSP00000518176.1	A0AA34QVH0
PCSK9	ENST00000713786.1		c.10G>A	p.Val4Ile	missense	Exon 1 of 13	ENSP00000519088.1	A0AAQ5BGX4

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00193

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:

0.000140

AC:

AN:

171484

AF XY:

0.000175

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00183

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000202

AC:

286

AN:

1413248

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

150

AN XY:

698290

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32740

American (AMR)

AF:

0.00

AC:

AN:

36912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00747

AC:

281

AN:

37626

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80362

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4480

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088044

Other (OTH)

AF:

0.0000512

AC:

AN:

58582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000656

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000129

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypercholesterolemia, autosomal dominant, 3 (2)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Hypercholesterolemia, familial, 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

6.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.065

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.48

M_CAP

Benign

0.018

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-0.32

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.35

Sift

Benign

0.27

Sift4G

Benign

0.44

Polyphen

0.32

Vest4

0.66

MVP

0.40

MPC

0.19

ClinPred

0.038

GERP RS

1.1

PromoterAI

0.031

Neutral

(source)

Varity_R

0.046

gMVP

0.39

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over