rs7374540

Positions:

• chr3-38592651-C-A
• chr3-38592651-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000423572.7(SCN5A):​c.2262+5078G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 151,914 control chromosomes in the GnomAD database, including 20,717 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20717 hom., cov: 31)
• Consequence: SCN5A ENST00000423572.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.509

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.2262+5078G>T		intron_variant		ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.2262+5078G>T		intron_variant		ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2262+5078G>T		intron_variant		5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.2262+5078G>T		intron_variant		1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75400 AN: 151796 Hom.: 20698 Cov.: 31

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.541

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.509

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.497 AC: 75445 AN: 151914 Hom.: 20717 Cov.: 31 AF XY: 0.501 AC XY: 37183 AN XY: 74244

Gnomad4 AFR AF: 0.242

Gnomad4 AMR AF: 0.541

Gnomad4 ASJ AF: 0.571

Gnomad4 EAS AF: 0.479

Gnomad4 SAS AF: 0.575

Gnomad4 FIN AF: 0.583

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.514

Alfa AF: 0.590 Hom.: 36793

Bravo AF: 0.477

Asia WGS AF: 0.517 AC: 1797 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.70
DANN	Benign	0.29

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: rs7374540; hg19: chr3-38634142;