3-38614542-A-G

Position:

• chr3-38614542-A-G

Variant summary

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

The NM_001099404.2(SCN5A):​c.612-476T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 155,130 control chromosomes in the GnomAD database, including 29,370 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 (28779 hom., cov: 33)
  • Exomes 𝑓: 0.61 (591 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.160

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_000335.5	c.612-708T>C		intron_variant		ENST00000423572.7	NP_000326.2
SCN5A	NM_001099404.2	c.612-476T>C		intron_variant		ENST00000413689.6	NP_001092874.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.612-476T>C		intron_variant		5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.612-708T>C		intron_variant		1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92832 AN: 151942 Hom.: 28739 Cov.: 33

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.585

GnomAD4 exome AF: 0.609 AC: 1870 AN: 3070 Hom.: 591 Cov.: 0 AF XY: 0.596 AC XY: 1002 AN XY: 1680

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.633

Gnomad4 ASJ exome AF: 0.540

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.600

Gnomad4 FIN exome AF: 0.565

Gnomad4 NFE exome AF: 0.625

Gnomad4 OTH exome AF: 0.576

GnomAD4 genome AF: 0.611 AC: 92922 AN: 152060 Hom.: 28779 Cov.: 33 AF XY: 0.606 AC XY: 44998 AN XY: 74310

Gnomad4 AFR AF: 0.684

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.357

Gnomad4 SAS AF: 0.537

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.600

Gnomad4 OTH AF: 0.584

Alfa AF: 0.603 Hom.: 38103

Bravo AF: 0.616

Asia WGS AF: 0.480 AC: 1672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.8
DANN	Benign	0.72

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: rs6797133; hg19: chr3-38656033; COSMIC: COSV61127505; COSMIC: COSV61127505;