rs11800231

chr1-55052267-G-Achr1-55052267-G-T

Variant summary

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

The NM_174936.4(PCSK9):c.524-11G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0495 in 1,613,694 control chromosomes in the GnomAD database, including 2,863 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (772 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2091 hom.)
• Consequence: PCSK9 NM_174936.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006677
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0920

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-55052267-G-A is Benign according to our data. Variant chr1-55052267-G-A is described in ClinVar as [Benign]. Clinvar id is 36671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052267-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCSK9	NM_174936.4	c.524-11G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000302118.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCSK9	ENST00000302118.5	c.524-11G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_174936.4	P2

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11959 AN: 151994 Hom.: 773 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0297

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0426

Gnomad OTH AF: 0.0833

GnomAD3 exomes AF: 0.0522 AC: 13121 AN: 251344 Hom.: 559 AF XY: 0.0496 AC XY: 6742 AN XY: 135844

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0295

Gnomad SAS exome AF: 0.0445

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0457

Gnomad OTH exome AF: 0.0552

GnomAD4 exome AF: 0.0464 AC: 67857 AN: 1461582 Hom.: 2091 Cov.: 35 AF XY: 0.0460 AC XY: 33463 AN XY: 727088

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0363

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.0263

Gnomad4 SAS exome AF: 0.0418

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0429

Gnomad4 OTH exome AF: 0.0548

GnomAD4 genome AF: 0.0787 AC: 11970 AN: 152112 Hom.: 772 Cov.: 32 AF XY: 0.0747 AC XY: 5558 AN XY: 74366

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0469

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.0296

Gnomad4 SAS AF: 0.0426

Gnomad4 FIN AF: 0.0176

Gnomad4 NFE AF: 0.0426

Gnomad4 OTH AF: 0.0834

Alfa AF: 0.0655 Hom.: 128

Bravo AF: 0.0862

Asia WGS AF: 0.0560 AC: 196 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	Mar 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

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. -

Familial hypercholesterolemia Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Feb 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.8
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
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: rs11800231; hg19: chr1-55517940;