rs2495482

Positions:

• chr1-55040059-A-G
• chr1-55040059-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407246.1(PCSK9):​c.-513A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.944 in 1,553,126 control chromosomes in the GnomAD database, including 692,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.92 (64013 hom., cov: 38)
  • Exomes 𝑓: 0.95 (628779 hom.)
• Consequence: PCSK9 NM_001407246.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 0.224

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-55040059-A-G is Benign according to our data. Variant chr1-55040059-A-G is described in ClinVar as [Benign]. Clinvar id is 262904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55040059-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.207+15A>G		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.207+15A>G		intron_variant		1	NM_174936.4	ENSP00000303208.5
PCSK9	ENST00000710286.1	c.564+15A>G		intron_variant				ENSP00000518176.1
PCSK9	ENST00000673726.1	n.207+15A>G		intron_variant				ENSP00000501004.1
PCSK9	ENST00000673913.2	n.207+15A>G		intron_variant				ENSP00000501161.2

Frequencies

GnomAD3 genomes AF: 0.915 AC: 139342 AN: 152240 Hom.: 63976 Cov.: 38

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.929

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.973

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.920

Gnomad NFE AF: 0.951

Gnomad OTH AF: 0.921

GnomAD3 exomes AF: 0.928 AC: 147203 AN: 158652 Hom.: 68556 AF XY: 0.936 AC XY: 79055 AN XY: 84504

Gnomad AFR exome AF: 0.830

Gnomad AMR exome AF: 0.836

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.941

Gnomad SAS exome AF: 0.970

Gnomad FIN exome AF: 0.965

Gnomad NFE exome AF: 0.951

Gnomad OTH exome AF: 0.942

GnomAD4 exome AF: 0.947 AC: 1326590 AN: 1400768 Hom.: 628779 Cov.: 65 AF XY: 0.949 AC XY: 655717 AN XY: 691306

Gnomad4 AFR exome AF: 0.824

Gnomad4 AMR exome AF: 0.844

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.957

Gnomad4 SAS exome AF: 0.970

Gnomad4 FIN exome AF: 0.965

Gnomad4 NFE exome AF: 0.952

Gnomad4 OTH exome AF: 0.941

GnomAD4 genome AF: 0.915 AC: 139434 AN: 152358 Hom.: 64013 Cov.: 38 AF XY: 0.917 AC XY: 68323 AN XY: 74510

Gnomad4 AFR AF: 0.835

Gnomad4 AMR AF: 0.902

Gnomad4 ASJ AF: 0.929

Gnomad4 EAS AF: 0.943

Gnomad4 SAS AF: 0.973

Gnomad4 FIN AF: 0.969

Gnomad4 NFE AF: 0.951

Gnomad4 OTH AF: 0.921

Alfa AF: 0.919 Hom.: 13492

Bravo AF: 0.904

Asia WGS AF: 0.953 AC: 3315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	-	- -

Hypercholesterolemia, familial, 1 Benign:3

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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.8
DANN	Benign	0.46
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		1.9

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

Other links and lift over

dbSNP: rs2495482; hg19: chr1-55505732;