rs1805126

chr3-38550915-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001099404.2(SCN5A):c.5457T>C(p.Asp1819=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,600 control chromosomes in the GnomAD database, including 110,517 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16131 hom., cov: 31)
  • Exomes 𝑓: 0.35 (94386 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: -2.12

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-38550915-A-G is Benign according to our data. Variant chr3-38550915-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 48307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38550915-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.5457T>C	p.Asp1819=	synonymous_variant	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5454T>C	p.Asp1818=	synonymous_variant	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5457T>C	p.Asp1819=	synonymous_variant	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5454T>C	p.Asp1818=	synonymous_variant	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66453 AN: 151806 Hom.: 16085 Cov.: 31

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.326

Gnomad OTH AF: 0.421

GnomAD3 exomes AF: 0.387 AC: 96582 AN: 249672 Hom.: 19834 AF XY: 0.379 AC XY: 51299 AN XY: 135390

Gnomad AFR exome AF: 0.654

Gnomad AMR exome AF: 0.376

Gnomad ASJ exome AF: 0.341

Gnomad EAS exome AF: 0.558

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.353 AC: 515661 AN: 1461676 Hom.: 94386 Cov.: 65 AF XY: 0.351 AC XY: 255503 AN XY: 727116

Gnomad4 AFR exome AF: 0.663

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.442

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.438 AC: 66548 AN: 151924 Hom.: 16131 Cov.: 31 AF XY: 0.439 AC XY: 32609 AN XY: 74256

Gnomad4 AFR AF: 0.651

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.326

Gnomad4 OTH AF: 0.419

Alfa AF: 0.355 Hom.: 23142

Bravo AF: 0.448

Asia WGS AF: 0.442 AC: 1539 AN: 3478

EpiCase AF: 0.342

EpiControl AF: 0.340

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Asp1819Asp in Exon 28 of SCN5A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence and has been identified in 38.2% (1388/3636) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1805126). -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jul 11, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 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. -

not provided Benign:3

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: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. -

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 09, 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. -

Cardiac arrhythmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.020
Dann	Benign	0.48

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: rs1805126; hg19: chr3-38592406; COSMIC: COSV61133328; COSMIC: COSV61133328;