1-55058524-A-G

Position:

• chr1-55058524-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_174936.4(PCSK9):​c.1380A>G​(p.Val460=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,612,026 control chromosomes in the GnomAD database, including 560,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52811 hom., cov: 32)
  • Exomes 𝑓: 0.83 (507719 hom.)
• Consequence: PCSK9 NM_174936.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.50

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 1-55058524-A-G is Benign according to our data. Variant chr1-55058524-A-G is described in ClinVar as [Benign]. Clinvar id is 201126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55058524-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.1380A>G	p.Val460=	synonymous_variant	9/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.1380A>G	p.Val460=	synonymous_variant	9/12	1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126484 AN: 152014 Hom.: 52779 Cov.: 32

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.883

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.831

Gnomad OTH AF: 0.856

GnomAD3 exomes AF: 0.857 AC: 215309 AN: 251326 Hom.: 92547 AF XY: 0.854 AC XY: 116064 AN XY: 135874

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.915

Gnomad ASJ exome AF: 0.814

Gnomad EAS exome AF: 0.993

Gnomad SAS exome AF: 0.874

Gnomad FIN exome AF: 0.827

Gnomad NFE exome AF: 0.832

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.833 AC: 1216466 AN: 1459894 Hom.: 507719 Cov.: 94 AF XY: 0.834 AC XY: 605989 AN XY: 726242

Gnomad4 AFR exome AF: 0.790

Gnomad4 AMR exome AF: 0.911

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.979

Gnomad4 SAS exome AF: 0.874

Gnomad4 FIN exome AF: 0.829

Gnomad4 NFE exome AF: 0.824

Gnomad4 OTH exome AF: 0.836

GnomAD4 genome AF: 0.832 AC: 126571 AN: 152132 Hom.: 52811 Cov.: 32 AF XY: 0.834 AC XY: 61993 AN XY: 74364

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.883

Gnomad4 ASJ AF: 0.815

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.831

Gnomad4 OTH AF: 0.858

Alfa AF: 0.830 Hom.: 66707

Bravo AF: 0.834

Asia WGS AF: 0.923 AC: 3209 AN: 3476

EpiCase AF: 0.829

EpiControl AF: 0.825

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:5

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Hypercholesterolemia, familial, 1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2017	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial hypercholesterolemia Benign:2

Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 01, 2022	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -

Hypobetalipoproteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2015

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	-0.62
CADD	Benign	8.9
DANN	Benign	0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs540796; hg19: chr1-55524197; COSMIC: COSV56161303;