rs544057915

chr3-38581273-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001099404.2(SCN5A):c.2886C>T(p.Ala962=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: SCN5A NM_001099404.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.724

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-38581273-G-A is Benign according to our data. Variant chr3-38581273-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 242191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.724 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.2886C>T	p.Ala962=	synonymous_variant	17/28	ENST00000413689.6
SCN5A	NM_000335.5	c.2886C>T	p.Ala962=	synonymous_variant	17/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.2886C>T	p.Ala962=	synonymous_variant	17/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.2886C>T	p.Ala962=	synonymous_variant	17/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 4 AN: 149050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000696

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000394

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000485

GnomAD3 exomes AF: 0.0000284 AC: 7 AN: 246830 Hom.: 0 AF XY: 0.0000224 AC XY: 3 AN XY: 134006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000392

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459518 Hom.: 0 Cov.: 36 AF XY: 0.00000965 AC XY: 7 AN XY: 725680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000268 AC: 4 AN: 149168 Hom.: 0 Cov.: 32 AF XY: 0.0000276 AC XY: 2 AN XY: 72442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000695

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000395

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -

Cardiac arrhythmia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	- -

Brugada syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Nov 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	8.8
Dann	Benign	0.68

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: rs544057915; hg19: chr3-38622764; COSMIC: COSV100348281;