1-55039879-ACTGCTGCTG-ACTGCTGCTGCTG

Position:

• chr1-55039879-ACTGCTGCTG-ACTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_174936.4(PCSK9):​c.63_65dup​(p.Leu22dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,557,874 control chromosomes in the GnomAD database, including 14,501 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P14P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1818 hom., cov: 31)
  • Exomes 𝑓: 0.14 (12683 hom.)
• Consequence: PCSK9 NM_174936.4 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.246

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 -16 ACMG points.

• BP6: Variant 1-55039879-A-ACTG is Benign according to our data. Variant chr1-55039879-A-ACTG is described in ClinVar as [Likely_benign]. Clinvar id is 235043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.63_65dup	p.Leu22dup	inframe_insertion	1/12	ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.63_65dup	p.Leu22dup	inframe_insertion	1/12	1	NM_174936.4	P2
PCSK9	ENST00000710286.1	c.420_422dup	p.Leu141dup	inframe_insertion	1/12			A2
PCSK9	ENST00000673726.1	c.63_65dup	p.Leu22dup	inframe_insertion, NMD_transcript_variant	1/6
PCSK9	ENST00000673913.2	c.63_65dup	p.Leu22dup	inframe_insertion, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23110 AN: 152038 Hom.: 1811 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.293

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.122 AC: 19607 AN: 161082 Hom.: 909 AF XY: 0.123 AC XY: 10578 AN XY: 86248

Gnomad AFR exome AF: 0.180

Gnomad AMR exome AF: 0.0770

Gnomad ASJ exome AF: 0.161

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.140 AC: 197297 AN: 1405720 Hom.: 12683 Cov.: 30 AF XY: 0.140 AC XY: 97431 AN XY: 694280

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0817

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0938

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.139

GnomAD4 genome AF: 0.152 AC: 23137 AN: 152154 Hom.: 1818 Cov.: 31 AF XY: 0.148 AC XY: 11020 AN XY: 74402

Gnomad4 AFR AF: 0.208

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.150

Gnomad4 FIN AF: 0.0863

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.144

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 30, 2013	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.63_65dupGCT in PCKS9 (aka c.61_63dupCTG, c.43_44insCTG, L21dup, L10, p.L15_16insL). This is an in-frame duplication of three nucleotides which results in insertion of a leucine in a 9-leucine track. The variant has been seen in at least 8 unrelated cases of familial hypercholesterolemia however it has also been observed at appreciable frequencies in individuals from the general population with normal cholesterol. Noguchi et al (2010) reported that 8 of 55 familial hypercholesterolemia patients without LDLR variants were heterozygous for this variant. No segregation or control data was provided. In total the variant has been seen in the homozygous state in 11 of 822 individuals and in the heterozygous state in 204 of 822 individuals from published reports and publicly available population datasets. The variant is listed in dbSNP as rs35574083 without minor allele frequency data. Another dbSNP entry, rs45454392, also represents a leucine insertion in the same track of leucine repeats, denoted c.44_45insGCT (p.Leu15delinsLeuLeu). These variants are likely synonymous as it would be impossible to know exactly where the insertion occurred in the repeat track and different groups would choose to number at different points in the track, but with both insertions leading to an additional leucine. The latter dbSNP entry includes minor allele frequency data from general populations samples in the Coriell repository with 2/24 African Americans being homozygotes for the insertion and 9/24 African American and 4/23 European individuals noted as heterozygotes. Chen et al (2005) reported allele frequencies for the L9, L10, and L11 variants in the Lipoprotein Coronary Atherosclerosis Study population (LCAS). The sample consistent of 372 35-75yo individuals with LDL-C levels of 115 to 190 mg/dL despite diet and one more coronary lesions of 30-75% stenosis.. Given this selection criteria this cannot be considered a general population sample, however their LDL levels indicate they likely did not have familial hypercholesterolemia. 90/372 individuals studied were heterozygotes for the L10 variant. Yue et al (2006) reported that in a general population sample with normal cholesterol phenotypes 101/403 individuals were heterozygoes for the L10 allele and 9/403 were homozygous. Unfortunately the NHLBI Exome Sequencing Project dataset only reports single nucleotide variation so no data is provided on this variant. Yue et al (2006) found that the variant is associated with lower LDL-C in a Caucasian sample with normal cholesterol. Individuals who had one 9 repeat copy and one 10 repeat copy (i.e. heterozygotes for this variant) had LDL-C that was 10-15 mg/dL lower. They found the 10 repeat variant was an independent predictor of LDL-C. Pisciotta et al (2011) compared total cholesterol LDL-C levels in familial hypercholesterolemia patients who were heterozygous for the 10 repeat variant with those who were homozygous for the wildtype 9 repeat variant and found no differences. However, in the subgroup of individuals treated with statins, the reduction in both total cholesterol and LDL-C was greater in heterozygotes for L10 than in wildtype homozygotes. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hypercholesterolemia, familial, 1 Benign:4

Benign, criteria provided, single submitter	research	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	MAF = 9% in 100 subjects with average plasma cholesterol -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 07, 2017	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
Benign, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2016	This variant is associated with the following publications: (PMID: 29562810, 30782561, 26687699, 25239117, 23743349, 16619215, 23663650, 20006333) -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 20, 2023	- -

Familial hypercholesterolemia Benign:3

Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Feb 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jul 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 21, 2018	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 26, 2016	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35574083; hg19: chr1-55505552;