rs7374391

chr3-38556844-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001099404.2(SCN5A):c.4300-266G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0963 in 152,138 control chromosomes in the GnomAD database, including 773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.096 (773 hom., cov: 32)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.842

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-38556844-C-T is Benign according to our data. Variant chr3-38556844-C-T is described in ClinVar as [Benign]. Clinvar id is 680774.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4297-266G>A		intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.4300-266G>A		intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4300-266G>A		intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4297-266G>A		intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.0962 AC: 14631 AN: 152020 Hom.: 771 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0640

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.0834

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.0818

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

GnomAD4 genome AF: 0.0963 AC: 14646 AN: 152138 Hom.: 773 Cov.: 32 AF XY: 0.0971 AC XY: 7223 AN XY: 74404

Gnomad4 AFR AF: 0.0768

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.0640

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.0828

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.0942

Gnomad4 OTH AF: 0.0805

Alfa AF: 0.0984 Hom.: 111

Bravo AF: 0.0964

Asia WGS AF: 0.115 AC: 400 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	6.5
Dann	Benign	0.46

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: rs7374391; hg19: chr3-38598335; COSMIC: COSV61138697; COSMIC: COSV61138697;