chr3-38603929-T-C

Position:

• chr3-38603929-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The ENST00000423572.7(SCN5A):​c.1673A>G​(p.His558Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,720 control chromosomes in the GnomAD database, including 43,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H558C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4753 hom., cov: 32)
  • Exomes 𝑓: 0.23 (39221 hom.)
• Consequence: SCN5A ENST00000423572.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:28 O:1
• Conservation: PhyloP100: 1.28

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.8279 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.002580464).
• BP6: Variant 3-38603929-T-C is Benign according to our data. Variant chr3-38603929-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 48289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38603929-T-C is described in Lovd as [Benign]. Variant chr3-38603929-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1673A>G	p.His558Arg	missense_variant	12/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1673A>G	p.His558Arg	missense_variant	12/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1673A>G	p.His558Arg	missense_variant	12/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.1673A>G	p.His558Arg	missense_variant	12/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37263 AN: 151978 Hom.: 4732 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.240

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.220 AC: 54882 AN: 249044 Hom.: 6383 AF XY: 0.223 AC XY: 30153 AN XY: 135142

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.201

Gnomad EAS exome AF: 0.0933

Gnomad SAS exome AF: 0.247

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.230 AC: 335541 AN: 1461624 Hom.: 39221 Cov.: 35 AF XY: 0.231 AC XY: 167767 AN XY: 727106

Gnomad4 AFR exome AF: 0.294

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.197

Gnomad4 EAS exome AF: 0.0938

Gnomad4 SAS exome AF: 0.240

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.233

GnomAD4 genome AF: 0.246 AC: 37344 AN: 152096 Hom.: 4753 Cov.: 32 AF XY: 0.245 AC XY: 18242 AN XY: 74342

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.240

Gnomad4 OTH AF: 0.241

Alfa AF: 0.235 Hom.: 10325

Bravo AF: 0.249

TwinsUK AF: 0.234 AC: 869

ALSPAC AF: 0.230 AC: 885

ESP6500AA AF: 0.275 AC: 1151

ESP6500EA AF: 0.232 AC: 1957

ExAC AF: 0.221 AC: 26760

Asia WGS AF: 0.202 AC: 702 AN: 3478

EpiCase AF: 0.246

EpiControl AF: 0.234

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:28 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 09, 2012	27% (1151/5339) of Afr Amer chrom in ESP -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Mar 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2014	- -

not provided Pathogenic:1 Benign:6 Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:10807545;PMID:11463728;PMID:11997281;PMID:12569159;PMID:12639704;PMID:14760488;PMID:14985827;PMID:15161528;PMID:15599693;PMID:15689442;PMID:16132053;PMID:16155735;PMID:16239976;PMID:16712702;PMID:17161064;PMID:17210839;PMID:17675083;PMID:17993325;PMID:18093912;PMID:18156160;PMID:18362431;PMID:18426444;PMID:19083750;PMID:19841300;PMID:20129283). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jul 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2022	See Variant Classification Assertion Criteria. -
Pathogenic, no assertion criteria provided	research	Biology Molecular and Stem Cell Facilities Laboratory, National Cardiovascular Center, Harapan Kita Hospital	-	Allele Freq Eas (0.1012); Sift: tolerated (1); PolyPhen: benign (0) -
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:3

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	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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. -

SUDDEN INFANT DEATH SYNDROME;C1832680:Dilated cardiomyopathy 1E;C1837845:Sick sinus syndrome 1;C1859062:Long QT syndrome 3;C1879286:Progressive familial heart block, type 1A;C2751898:Ventricular fibrillation, paroxysmal familial, type 1;C3151464:Atrial fibrillation, familial, 10;C4551804:Brugada syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

Congenital long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

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, criteria provided, single submitter

clinical testing

Cohesion Phenomics

Sep 27, 2022

- -

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. -

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. -

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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	1.1
DANN	Benign	0.29
DEOGEN2	Benign	0.41	.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.19	.;T;T;T;T;T;T;.;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.6	.;N;.;.;.;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	3.9	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.029
MPC		0.42
ClinPred		0.0038	T
GERP RS		2.4
Varity_R		0.032
gMVP		0.70

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: rs1805124; hg19: chr3-38645420; COSMIC: COSV61125544;