dbSNP rs72646509: PCSK9:p.Pro279Thr (chr1-55056028-C-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_001407240.1(PCSK9):c.958C>A(p.Pro320Thr) 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. P320L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 2 hom. )

Consequence

PCSK9
NM_001407240.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.85

Publications

5 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=0.009918392).

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 VariationId is 375846.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00115 (175/152296) while in subpopulation AFR AF = 0.00387 (161/41556). AF 95% confidence interval is 0.00339. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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_001407240.1. 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.835C>A	p.Pro279Thr	missense	Exon 6 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.958C>A	p.Pro320Thr	missense	Exon 7 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.835C>A	p.Pro279Thr	missense	Exon 6 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.835C>A	p.Pro279Thr	missense	Exon 6 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1192C>A	p.Pro398Thr	missense	Exon 6 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.958C>A	p.Pro320Thr	missense	Exon 7 of 13	ENSP00000519088.1

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

GnomAD2 exomes

AF:

0.000308

AC:

AN:

243220

AF XY:

0.000212

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 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

African (AFR)

AF:

0.00401

AC:

134

AN:

33406

American (AMR)

AF:

0.000404

AC:

AN:

44608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.00

AC:

AN:

85826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53032

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1109588

Other (OTH)

AF:

0.000366

AC:

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.00115

AC:

175

AN:

152296

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00387

AC:

161

AN:

41556

American (AMR)

AF:

0.000653

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000760

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

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)

not provided (2)

Cardiovascular phenotype (1)

Familial hypercholesterolemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

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

PhyloP100

3.8

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

Mutation Taster

=31/69

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