rs11800243

Positions:

• chr1-55052420-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_174936.4(PCSK9):​c.657+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,613,596 control chromosomes in the GnomAD database, including 1,669 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 0.040 (150 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1519 hom.)
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.163

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-55052420-G-A is Benign according to our data. Variant chr1-55052420-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262906.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, Uncertain_significance=1}. Variant chr1-55052420-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.657+9G>A		intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.657+9G>A		intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6132 AN: 152080 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0931

Gnomad EAS AF: 0.0299

Gnomad SAS AF: 0.0450

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0546

GnomAD3 exomes AF: 0.0419 AC: 10495 AN: 250622 Hom.: 290 AF XY: 0.0423 AC XY: 5737 AN XY: 135612

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0980

Gnomad EAS exome AF: 0.0293

Gnomad SAS exome AF: 0.0467

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0454

Gnomad OTH exome AF: 0.0517

GnomAD4 exome AF: 0.0427 AC: 62460 AN: 1461398 Hom.: 1519 Cov.: 35 AF XY: 0.0429 AC XY: 31197 AN XY: 727004

Gnomad4 AFR exome AF: 0.0413

Gnomad4 AMR exome AF: 0.0294

Gnomad4 ASJ exome AF: 0.0973

Gnomad4 EAS exome AF: 0.0263

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0428

Gnomad4 OTH exome AF: 0.0472

GnomAD4 genome AF: 0.0403 AC: 6139 AN: 152198 Hom.: 150 Cov.: 32 AF XY: 0.0386 AC XY: 2874 AN XY: 74422

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.0931

Gnomad4 EAS AF: 0.0298

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.0424

Gnomad4 OTH AF: 0.0550

Alfa AF: 0.0476 Hom.: 97

Bravo AF: 0.0428

Asia WGS AF: 0.0490 AC: 171 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypercholesterolemia, familial, 1 Uncertain:1 Benign:2

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

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2017	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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Familial hypercholesterolemia Benign:2

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

Hypobetalipoproteinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 08, 2014

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	-0.84
CADD	Benign	4.4
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs11800243; hg19: chr1-55518093;