rs6791924

Positions:

• chr3-38633208-G-A
• chr3-38633208-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001099404.2(SCN5A):​c.100C>T​(p.Arg34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0062 in 1,613,396 control chromosomes in the GnomAD database, including 388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (211 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (177 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 2.63

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 -17 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 130) in uniprot entity SCN5A_HUMAN there are 19 pathogenic changes around while only 2 benign (90%) in NM_001099404.2
• 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 4.7729 (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=0.0023889542).
• BP6: Variant 3-38633208-G-A is Benign according to our data. Variant chr3-38633208-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 48279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38633208-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.100C>T	p.Arg34Cys	missense_variant	2/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.100C>T	p.Arg34Cys	missense_variant	2/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.100C>T	p.Arg34Cys	missense_variant	2/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.100C>T	p.Arg34Cys	missense_variant	2/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4364 AN: 152102 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.0969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.00817 AC: 2031 AN: 248650 Hom.: 72 AF XY: 0.00639 AC XY: 863 AN XY: 134992

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00696

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00646

GnomAD4 exome AF: 0.00386 AC: 5634 AN: 1461174 Hom.: 177 Cov.: 31 AF XY: 0.00352 AC XY: 2555 AN XY: 726878

Gnomad4 AFR exome AF: 0.0995

Gnomad4 AMR exome AF: 0.00839

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.00825

GnomAD4 genome AF: 0.0287 AC: 4375 AN: 152222 Hom.: 211 Cov.: 32 AF XY: 0.0278 AC XY: 2069 AN XY: 74432

Gnomad4 AFR AF: 0.0969

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00124

Gnomad4 OTH AF: 0.0266

Alfa AF: 0.00682 Hom.: 47

Bravo AF: 0.0324

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.0888 AC: 352

ESP6500EA AF: 0.00133 AC: 11

ExAC AF: 0.00935 AC: 1130

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

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:11997281;PMID:17161064;PMID:17675083;PMID:17993325;PMID:19841300;PMID:20129283). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2020	This variant is associated with the following publications: (PMID: 25119684, 27884173) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Arg34Cys in Exon 02 of SCN5A: This variant is not expected to have clinical si gnificance because it has been identified in 9.0% (296/3276) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs6791924). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Brugada syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 23, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

Jan 23, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

Jan 23, 2018

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

Jan 23, 2018

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

Jan 23, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

Jun 25, 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

Jan 23, 2018

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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;.;.;.;D;.;.;.;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;.;D;D;D
MetaRNN	Benign	0.0024	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.2	.;M;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;.;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;.;D;.;D;D;.;.;.;.
Vest4		0.65
MVP		0.76
MPC		1.2
ClinPred		0.029	T
GERP RS		4.5
Varity_R		0.28
gMVP		0.51

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: rs6791924; hg19: chr3-38674699;