1-55052697-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_174936.4(PCSK9):c.705C>T(p.Ser235Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,082 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.022 ( 127 hom., cov: 35)

Exomes 𝑓: 0.0024 ( 141 hom. )

Consequence

PCSK9
NM_174936.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -1.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 1-55052697-C-T is Benign according to our data. Variant chr1-55052697-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265932.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Uncertain_significance=1}. Variant chr1-55052697-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.05 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.705C>T	p.Ser235Ser	synonymous_variant	Exon 5 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.705C>T	p.Ser235Ser	synonymous_variant	Exon 5 of 12	1	NM_174936.4	ENSP00000303208.5		Q8NBP7-1

Frequencies

GnomAD3 genomes

AF:

0.0224

AC:

3405

AN:

152210

Hom.:

127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00884

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.00584

AC:

1454

AN:

249132

Hom.:

AF XY:

0.00437

AC XY:

591

AN XY:

135138

show subpopulations

Gnomad AFR exome

AF:

0.0808

Gnomad AMR exome

AF:

0.00313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000286

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00243

AC:

3551

AN:

1460754

Hom.:

141

Cov.:

AF XY:

0.00212

AC XY:

1538

AN XY:

726682

show subpopulations

Gnomad4 AFR exome

AF:

0.0830

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.000133

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.00578

GnomAD4 genome

AF:

0.0224

AC:

3419

AN:

152328

Hom.:

127

Cov.:

AF XY:

0.0219

AC XY:

1634

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0775

Gnomad4 AMR

AF:

0.00882

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0129

Hom.:

Bravo

AF:

0.0257

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:1Benign:2

Mar 01, 2016

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jun 02, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, autosomal dominant, 3

Benign:3

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jul 28, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over