chr1-55056186-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_StrongBP6_Very_StrongBP7BS1BS2_Supporting

The NM_174936.4(PCSK9):c.993C>T(p.Pro331Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000294 in 1,457,672 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P331P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -3.07

Publications

2 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 1-55056186-C-T is Benign according to our data. Variant chr1-55056186-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 496568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.07 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000287 (43/149774) while in subpopulation EAS AF = 0.00322 (16/4964). AF 95% confidence interval is 0.00202. There are 1 homozygotes in GnomAd4. There are 23 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.993C>T	p.Pro331Pro	synonymous_variant	Exon 6 of 12	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5 link	c.993C>T	p.Pro331Pro	synonymous_variant	Exon 6 of 12	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes

AF:

0.000287

AC:

AN:

149658

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000248

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00322

Gnomad SAS

AF:

0.00147

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000148

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.000597

AC:

AN:

120672

AF XY:

0.000635

show subpopulations

Gnomad AFR exome

AF:

0.000140

Gnomad AMR exome

AF:

0.000158

Gnomad ASJ exome

AF:

0.00197

Gnomad EAS exome

AF:

0.00351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000294

AC:

385

AN:

1307898

Hom.:

Cov.:

AF XY:

0.000297

AC XY:

189

AN XY:

636958

show subpopulations

African (AFR)

AF:

0.0000337

AC:

AN:

29716

American (AMR)

AF:

0.0000623

AC:

AN:

32110

Ashkenazi Jewish (ASJ)

AF:

0.00201

AC:

AN:

20924

East Asian (EAS)

AF:

0.00464

AC:

157

AN:

33824

South Asian (SAS)

AF:

0.000610

AC:

AN:

65592

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44340

Middle Eastern (MID)

AF:

0.000505

AC:

AN:

3962

European-Non Finnish (NFE)

AF:

0.000103

AC:

105

AN:

1024238

Other (OTH)

AF:

0.000677

AC:

AN:

53192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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:

0.000287

AC:

AN:

149774

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

AN XY:

73032

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40486

American (AMR)

AF:

0.000201

AC:

AN:

14954

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3468

East Asian (EAS)

AF:

0.00322

AC:

AN:

4964

South Asian (SAS)

AF:

0.00147

AC:

AN:

4754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000148

AC:

AN:

67684

Other (OTH)

AF:

0.000483

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000619

Hom.:

Bravo

AF:

0.000404

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCSK9: BP4, BP7, BS1 -

Aug 07, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 09, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The PCSK9 c.993C>T (p.Pro331Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 27/22050 (1/816), predominantly in the Asian cohort, 19/4192 (1/222), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic PCSK9 variant of 1/53191 (0.0000188), suggesting this variant is a common polymorphism found in population(s) of Asian origin. The variant of interest has been reported in affected individuals via publications and classified as a common polymorphism. Therefore, the variant of interest has been classified as Benign. -

May 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 14727156, 18718593) -

not specified

Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Dec 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypercholesterolemia, familial, 1

Benign:1

Jan 02, 2018

Robarts Research Institute, Western University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 15, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Familial hypercholesterolemia

Benign:1

Dec 03, 2017

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

7.0

(source)

DANN

Benign

0.87

PhyloP100

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over