rs2483205

Positions:

• chr1-55052643-C-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.658-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,612,178 control chromosomes in the GnomAD database, including 154,963 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15442 hom., cov: 34)
  • Exomes 𝑓: 0.43 (139521 hom.)
• Consequence: PCSK9 NM_174936.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001414
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: -0.272

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=-0.89).
• BP6: Variant 1-55052643-C-T is Benign according to our data. Variant chr1-55052643-C-T is described in ClinVar as [Benign]. Clinvar id is 36672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-55052643-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.658-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.658-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_174936.4	ENSP00000303208	P2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67804 AN: 152030 Hom.: 15440 Cov.: 34

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.600

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.433

GnomAD3 exomes AF: 0.419 AC: 104152 AN: 248680 Hom.: 22697 AF XY: 0.425 AC XY: 57298 AN XY: 134798

Gnomad AFR exome AF: 0.489

Gnomad AMR exome AF: 0.319

Gnomad ASJ exome AF: 0.501

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.448

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.434 AC: 634366 AN: 1460030 Hom.: 139521 Cov.: 72 AF XY: 0.436 AC XY: 316773 AN XY: 726170

Gnomad4 AFR exome AF: 0.496

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.446

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.441

Gnomad4 OTH exome AF: 0.429

GnomAD4 genome AF: 0.446 AC: 67847 AN: 152148 Hom.: 15442 Cov.: 34 AF XY: 0.444 AC XY: 33048 AN XY: 74392

Gnomad4 AFR AF: 0.490

Gnomad4 AMR AF: 0.378

Gnomad4 ASJ AF: 0.495

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.445

Gnomad4 OTH AF: 0.430

Alfa AF: 0.447 Hom.: 23785

Bravo AF: 0.439

Asia WGS AF: 0.337 AC: 1177 AN: 3478

EpiCase AF: 0.455

EpiControl AF: 0.456

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, familial, 1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	research	Iberoamerican FH Network	Mar 01, 2016	- -
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, no assertion criteria provided	research	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	-	- -

Hypercholesterolemia, autosomal dominant, 3 Benign:4

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 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, 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	- -

not specified Benign:3

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. -

not provided Benign:2

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

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	- -

Short fetal femur length Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Phenosystems SA

-

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
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: rs2483205; hg19: chr1-55518316; COSMIC: COSV56162583;