rs41313703

Positions:

• chr3-38606741-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001099404.2(SCN5A):​c.1068T>C​(p.Asp356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,613,906 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:13
• Conservation: PhyloP100: 1.24

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-38606741-A-G is Benign according to our data. Variant chr3-38606741-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165156.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=9, Uncertain_significance=7}. Variant chr3-38606741-A-G is described in Lovd as [Benign]. Variant chr3-38606741-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 9 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1068T>C	p.Asp356=	synonymous_variant	9/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1068T>C	p.Asp356=	synonymous_variant	9/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1068T>C	p.Asp356=	synonymous_variant	9/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.1068T>C	p.Asp356=	synonymous_variant	9/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.00319 AC: 485 AN: 152194 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000731 AC: 182 AN: 249064 Hom.: 1 AF XY: 0.000585 AC XY: 79 AN XY: 135150

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000267 AC: 390 AN: 1461594 Hom.: 2 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727082

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152312 Hom.: 9 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74470

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 2

Bravo AF: 0.00392

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SCN5A: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Asp356Asp in Exon 09 of SCN5A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence and has been identified in 1.1% (37/3444) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs41313703). -

Cardiac arrhythmia Benign:2

Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 25, 2018	- -

Progressive familial heart block Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Paroxysmal familial ventricular fibrillation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Congenital long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sick sinus syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Brugada syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

in vitro;research

Roden Lab, Vanderbilt University Medical Center

-

We classified this variant using data from the calibrated functional assay 'ParSE-seq' (PMID: 37732247), population data, and in silico data within the ACMG v3 framework (PMID: 25741868)The SCN5A variant, 3-38606741-A-G was evaluated for association with the loss-of-function condition Brugada Syndrome.This Variant had an AF of 0.003186722 in gnomAD v3The in silico predictor SpliceAI scored the variant as 0; normal <0.2, likely damaging >0.5.Using the functional RNA-splicing assay, ParSE-seq, the variant was evaluated to have no impact on splicing (BS3_strong) following the Brnich et al. calibration framework (PMID: 31892348). We do not apply benign splicing functional data to missense variants. In aggregate, we therefore classify this variant as LB using these collective data. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 22, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.1
DANN	Benign	0.57

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: rs41313703; hg19: chr3-38648232;