dbSNP rs533555352: PCSK9:p.Arg680Trp (chr1-55063543-C-T) – 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.2038C>T(p.Arg680Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,094 control chromosomes in the GnomAD database, including 3 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. R680Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 3 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.157

Publications

1 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, 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022096336).

BP6

Variant 1-55063543-C-T is Benign according to our data. Variant chr1-55063543-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375843.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000167 (244/1460748) while in subpopulation SAS AF = 0.0024 (207/86188). AF 95% confidence interval is 0.00213. There are 3 homozygotes in GnomAdExome4. There are 176 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. 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
PCSK9	NM_174936.4	MANE Select	c.2038C>T	p.Arg680Trp	missense	Exon 12 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.2161C>T	p.Arg721Trp	missense	Exon 13 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.2080C>T	p.Arg694Trp	missense	Exon 12 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.2038C>T	p.Arg680Trp	missense	Exon 12 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.2395C>T	p.Arg799Trp	missense	Exon 12 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.2161C>T	p.Arg721Trp	missense	Exon 13 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152228

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:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000310

AC:

AN:

248286

AF XY:

0.000408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.0000465

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000167

AC:

244

AN:

1460748

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

726716

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00240

AC:

207

AN:

86188

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53236

Middle Eastern (MID)

AF:

0.000186

AC:

AN:

5382

European-Non Finnish (NFE)

AF:

0.0000198

AC:

AN:

1111692

Other (OTH)

AF:

0.000182

AC:

AN:

60308

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.0000525

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.0000805

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000404

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

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

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Benign

-0.030

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.6

PhyloP100

0.16

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.41

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.47

MutPred

0.51

Loss of disorder (P = 0)

MVP

0.88

MPC

0.85

ClinPred

0.18

GERP RS

-0.17

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.42

gMVP

0.82

Mutation Taster

=79/21

polymorphism

(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