chr1-55058635-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_ModerateBP6_Very_Strong

The NM_174936.4(PCSK9):c.1491C>T(p.Gly497Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,607,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0430

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: Likely_benign. The variant received -6 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 1-55058635-C-T is Benign according to our data. Variant chr1-55058635-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 413315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1491C>T	p.Gly497Gly	synonymous	Exon 9 of 12	NP_777596.2
PCSK9	NM_001407240.1		c.1614C>T	p.Gly538Gly	synonymous	Exon 10 of 13	NP_001394169.1
PCSK9	NM_001407241.1		c.1491C>T	p.Gly497Gly	synonymous	Exon 9 of 12	NP_001394170.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PCSK9	ENST00000302118.5	TSL:1 MANE Select	c.1491C>T	p.Gly497Gly	synonymous	Exon 9 of 12	ENSP00000303208.5
PCSK9	ENST00000710286.1		c.1848C>T	p.Gly616Gly	synonymous	Exon 9 of 12	ENSP00000518176.1
PCSK9	ENST00000713786.1		c.1614C>T	p.Gly538Gly	synonymous	Exon 10 of 13	ENSP00000519088.1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

150144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

Gnomad ASJ

AF:

0.000869

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00205

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000414

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.000355

AC:

AN:

245192

AF XY:

0.000338

show subpopulations

Gnomad AFR exome

AF:

0.000511

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00131

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.000182

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000197

AC:

287

AN:

1457854

Hom.:

Cov.:

109

AF XY:

0.000185

AC XY:

134

AN XY:

725116

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33362

American (AMR)

AF:

0.0000449

AC:

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39604

South Asian (SAS)

AF:

0.00

AC:

AN:

86010

European-Finnish (FIN)

AF:

0.00217

AC:

114

AN:

52638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4138

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1111344

Other (OTH)

AF:

0.000216

AC:

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000440

AC:

AN:

150144

Hom.:

Cov.:

AF XY:

0.000465

AC XY:

AN XY:

73166

show subpopulations

African (AFR)

AF:

0.000246

AC:

AN:

40612

American (AMR)

AF:

0.000199

AC:

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.000869

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

5074

South Asian (SAS)

AF:

0.00

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00205

AC:

AN:

10236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000414

AC:

AN:

67636

Other (OTH)

AF:

0.000484

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000564

Hom.:

Bravo

AF:

0.000200

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3

Benign:2

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 23, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PCSK9: PP3, BS2

Familial hypercholesterolemia

Benign:2

Jan 01, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 18, 2024

GENinCode PLC

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved. Therefore this variant has been classified as Likely Benign (BP4, BP7).

not specified

Benign:1

Aug 19, 2023

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jan 14, 2025

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.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

-0.043

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.96

Position offset: -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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over