NM_001099404.2:c.1518+221G>A

Variant names:

• chr3-38604508-C-T
• rs13084981
• NM_001099404.2:c.1518+221G>A

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.1518+221G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 152,146 control chromosomes in the GnomAD database, including 1,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1548 hom., cov: 32)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0870

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=-0.85).
• BP6: Variant 3-38604508-C-T is Benign according to our data. Variant chr3-38604508-C-T is described in ClinVar as [Benign]. Clinvar id is 678651.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.1518+221G>A		intron_variant	Intron 11 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.1518+221G>A		intron_variant	Intron 11 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.1518+221G>A		intron_variant	Intron 11 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.1518+221G>A		intron_variant	Intron 11 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19058 AN: 152028 Hom.: 1547 Cov.: 32

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.0757

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0877

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.132

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

GnomAD4 genome AF: 0.125 AC: 19066 AN: 152146 Hom.: 1548 Cov.: 32 AF XY: 0.131 AC XY: 9719 AN XY: 74356

Gnomad4 AFR AF: 0.0943

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.0877

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.132

Alfa AF: 0.112 Hom.: 916

Bravo AF: 0.122

Asia WGS AF: 0.290 AC: 1005 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.85
CADD	Benign	3.6
DANN	Benign	0.63

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: rs13084981; hg19: chr3-38645999;