rs41312391

Positions:

• chr3-38557115-C-A
• chr3-38557115-C-G
• chr3-38557115-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001099404.2(SCN5A):​c.4299+116G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 871,836 control chromosomes in the GnomAD database, including 15 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 0.0023 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (11 hom.)
• Consequence: SCN5A NM_001099404.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.496

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=-0.84).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00291 (2093/719708) while in subpopulation MID AF= 0.0202 (84/4162). AF 95% confidence interval is 0.0167. There are 11 homozygotes in gnomad4_exome. There are 1125 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_000335.5	c.4296+116G>T		intron_variant		ENST00000423572.7
SCN5A	NM_001099404.2	c.4299+116G>T		intron_variant		ENST00000413689.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.4299+116G>T		intron_variant		5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.4296+116G>T		intron_variant		1	NM_000335.5	A1

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152010 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00872

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00334

GnomAD4 exome AF: 0.00291 AC: 2093 AN: 719708 Hom.: 11 AF XY: 0.00301 AC XY: 1125 AN XY: 374002

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00603

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00577

Gnomad4 FIN exome AF: 0.00480

Gnomad4 NFE exome AF: 0.00248

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152128 Hom.: 4 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74370

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00872

Gnomad4 FIN AF: 0.00302

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000455 Hom.: 261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.36
DANN	Benign	0.51

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: rs41312391; hg19: chr3-38598606;