rs41312433

chr3-38606151-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_001099404.2(SCN5A):c.1141-3C>A variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.18 in 1,612,096 control chromosomes in the GnomAD database, including 26,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2225 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24351 hom.)
• Consequence: SCN5A NM_001099404.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 3.84

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 3-38606151-G-T is Benign according to our data. Variant chr3-38606151-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 48280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38606151-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.1141-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.1141-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1141-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1141-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25593 AN: 151920 Hom.: 2225 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0968

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.172 AC: 42640 AN: 248386 Hom.: 3784 AF XY: 0.174 AC XY: 23430 AN XY: 134824

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.0894

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.181 AC: 264271 AN: 1460058 Hom.: 24351 Cov.: 32 AF XY: 0.182 AC XY: 131857 AN XY: 726366

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0902

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.168 AC: 25601 AN: 152038 Hom.: 2225 Cov.: 32 AF XY: 0.170 AC XY: 12661 AN XY: 74314

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.179

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.0968

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.169

Alfa AF: 0.180 Hom.: 1089

Bravo AF: 0.165

Asia WGS AF: 0.156 AC: 542 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.188

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2011	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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	c.1141-3C>A in Intron 09 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 18.6% (1238/6660) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs41312433). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	Athena Diagnostics	Apr 20, 2017	- -

Brugada syndrome 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

Cardiac arrhythmia Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Ventricular fibrillation, paroxysmal familial, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Dilated cardiomyopathy 1E Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sick sinus syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Progressive familial heart block, type 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Primary dilated cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 27, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 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. -

Long QT syndrome 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	19
Dann	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.17		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: rs41312433; hg19: chr3-38647642; COSMIC: COSV61119351;