3-38582762-T-C

Variant names:

• chr3-38582762-T-C
• rs3922844
• NM_001099404.2:c.2788-1391A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001099404.2(SCN5A):​c.2788-1391A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 152,124 control chromosomes in the GnomAD database, including 30,202 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 0.61 (30202 hom., cov: 33)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 42 publications found

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]

SCN5A Gene-Disease associations (from GenCC):

• Brugada syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Brugada syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• dilated cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• dilated cardiomyopathy 1E

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• sick sinus syndrome 1

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• progressive familial heart block, type 1A

  Inheritance: SD, AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• atrial standstill

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial sick sinus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• paroxysmal familial ventricular fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• progressive familial heart block

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• short QT syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.2788-1391A>G		intron_variant	Intron 16 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.2788-1391A>G		intron_variant	Intron 16 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.2788-1391A>G		intron_variant	Intron 16 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.2788-1391A>G		intron_variant	Intron 16 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93493 AN: 152006 Hom.: 30206 Cov.: 33

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.672

Gnomad AMR AF: 0.634

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.623

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

GnomAD4 genome AF: 0.615 AC: 93520 AN: 152124 Hom.: 30202 Cov.: 33 AF XY: 0.619 AC XY: 46061 AN XY: 74362

African (AFR) AF: 0.401 AC: 16638 AN: 41498

American (AMR) AF: 0.633 AC: 9684 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2229 AN: 3472

East Asian (EAS) AF: 0.882 AC: 4548 AN: 5156

South Asian (SAS) AF: 0.736 AC: 3551 AN: 4822

European-Finnish (FIN) AF: 0.751 AC: 7962 AN: 10598

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.688 AC: 46776 AN: 67972

Other (OTH) AF: 0.624 AC: 1319 AN: 2114

Alfa AF: 0.672 Hom.: 144320

Bravo AF: 0.599

Asia WGS AF: 0.751 AC: 2609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.038
DANN	Benign	0.44
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3922844; hg19: chr3-38624253;