1-55039879-ACTGCTGCTG-ACTGCTG

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_174936.4(PCSK9):c.63_65delGCT(p.Leu22del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,553,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

PCSK9
NM_174936.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: -0.0410

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 1-55039879-ACTG-A is Benign according to our data. Variant chr1-55039879-ACTG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265917.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=2}. Variant chr1-55039879-ACTG-A is described in Lovd as [Benign]. Variant chr1-55039879-ACTG-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000631 (96/152182) while in subpopulation AMR AF= 0.00307 (47/15300). AF 95% confidence interval is 0.00237. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 96 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4 link	c.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 12	ENST00000302118.5	NP_777596.2	Q8NBP7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCSK9	ENST00000302118.5 link	c.63_65delGCT	p.Leu22del	disruptive_inframe_deletion	Exon 1 of 12	1	NM_174936.4	ENSP00000303208.5	Q8NBP7-1
PCSK9	ENST00000710286.1 link	c.420_422delGCT	p.Leu141del	disruptive_inframe_deletion	Exon 1 of 12			ENSP00000518176.1
PCSK9	ENST00000673726.1 link	n.63_65delGCT		non_coding_transcript_exon_variant	Exon 1 of 6			ENSP00000501004.1	A0A669KAY4
PCSK9	ENST00000673913.2 link	n.63_65delGCT		non_coding_transcript_exon_variant	Exon 1 of 12			ENSP00000501161.2	A0A669KB81

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000695

AC:

112

AN:

161082

Hom.:

AF XY:

0.000696

AC XY:

AN XY:

86248

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.000584

Gnomad SAS exome

AF:

0.000130

Gnomad FIN exome

AF:

0.000712

Gnomad NFE exome

AF:

0.000551

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000228

AC:

319

AN:

1401516

Hom.:

AF XY:

0.000227

AC XY:

157

AN XY:

692260

show subpopulations

Gnomad4 AFR exome

AF:

0.000749

Gnomad4 AMR exome

AF:

0.00151

Gnomad4 ASJ exome

AF:

0.000319

Gnomad4 EAS exome

AF:

0.0000545

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000391

Gnomad4 NFE exome

AF:

0.000149

Gnomad4 OTH exome

AF:

0.000688

GnomAD4 genome

AF:

0.000631

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.000747

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.00115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 1

Uncertain:2Benign:3

Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 01, 2016

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 02, 2018

Robarts Research Institute, Western University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not specified

Benign:2

Aug 13, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCSK9 c.63_65delGCT (p.Leu23del) results in an in-frame deletion that is predicted to remove a Leu amino acid from the encoded protein. The variant allele was found at a frequency of 0.0007 in 161082 control chromosomes. The observed variant frequency is approximately 35-folds over the estimated maximal expected allele frequency for a pathogenic variant in PCSK9 causing Early Onset Coronary Artery Disease phenotype (2e-05), strongly suggesting that the variant is benign. Five ClinVar submissions (evaluation after 2014) cites the variant three times as likely benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. -

Mar 11, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Sep 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 07, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 33303402, 29572815) -

Hypercholesterolemia, autosomal dominant, 3

Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCSK9-related disorder

Benign:1

Jun 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Jul 12, 2018

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 v4.3

Name

Calibrated prediction

Score

Prediction

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