rs28362263

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_174936.4(PCSK9):c.1327G>A(p.Ala443Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00507 in 1,613,318 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 186 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 151 hom. )

Consequence

PCSK9
NM_174936.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:15

Conservation

PhyloP100: 1.40

Publications

54 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014311075).

BP6

Variant 1-55058182-G-A is Benign according to our data. Variant chr1-55058182-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0919 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.1327G>A	p.Ala443Thr	missense_variant	Exon 8 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.1327G>A	p.Ala443Thr	missense_variant	Exon 8 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0272

AC:

4136

AN:

152204

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00903

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00719

AC:

1797

AN:

249780

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.0977

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.00269

Gnomad EAS exome

AF:

0.000763

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00277

AC:

4042

AN:

1460996

Hom.:

151

Cov.:

AF XY:

0.00239

AC XY:

1738

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.0927

AC:

3101

AN:

33470

American (AMR)

AF:

0.00487

AC:

218

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26134

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000190

AC:

AN:

52616

Middle Eastern (MID)

AF:

0.00348

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000272

AC:

302

AN:

1111964

Other (OTH)

AF:

0.00515

AC:

311

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

235

469

704

938

1173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

220

330

440

550

<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:

0.0272

AC:

4138

AN:

152322

Hom.:

186

Cov.:

AF XY:

0.0258

AC XY:

1920

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0943

AC:

3920

AN:

41558

American (AMR)

AF:

0.00901

AC:

138

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68022

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

194

388

582

776

970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00990

Hom.:

135

Bravo

AF:

0.0305

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0837

AC:

369

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00884

AC:

1073

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Uncertain:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:5

Sep 28, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 19, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dec 16, 2016

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

subjects mutated among 2600 FH index cases screened = 8 / Software predictions: Benign -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, familial, 1

Pathogenic:1Uncertain:1Benign:1

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance:Pathogenic

Review Status:flagged submission

Collection Method:research

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:research

- -

not provided

Benign:3

Jun 16, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16211558, 18680192, 23663650, 16909389, 29540175, 30899674, 29447211) -

Oct 16, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial hypercholesterolemia

Benign:2

May 17, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 09, 2023

Cohesion Phenomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hypobetalipoproteinemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Mar 23, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.085

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.68

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

1.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.49

REVEL

Benign

0.043

Sift

Benign

0.53

Sift4G

Benign

0.60

Polyphen

0.0040

Vest4

0.022

MVP

0.32

MPC

0.22

ClinPred

0.0012

GERP RS

-6.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.071

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over