3-38608969-T-C

Variant names:

• chr3-38608969-T-C
• rs6599223
• NM_001099404.2:c.935-755A>G

Variant summary

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

The NM_000335.5(SCN5A):​c.935-755A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 152,124 control chromosomes in the GnomAD database, including 52,002 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 0.83 (52002 hom., cov: 31)
• Consequence: SCN5A NM_000335.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500

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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.935-755A>G		intron_variant	Intron 7 of 27	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.935-755A>G		intron_variant	Intron 7 of 27	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.935-755A>G		intron_variant	Intron 7 of 27	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.935-755A>G		intron_variant	Intron 7 of 27	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes AF: 0.825 AC: 125457 AN: 152006 Hom.: 51956 Cov.: 31

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.916

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.813

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.824

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

GnomAD4 genome AF: 0.825 AC: 125553 AN: 152124 Hom.: 52002 Cov.: 31 AF XY: 0.821 AC XY: 61066 AN XY: 74336

Gnomad4 AFR AF: 0.822

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.813

Gnomad4 EAS AF: 0.665

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.841

Gnomad4 OTH AF: 0.823

Alfa AF: 0.840 Hom.: 85006

Bravo AF: 0.832

Asia WGS AF: 0.740 AC: 2577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.3
DANN	Benign	0.54

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: rs6599223; hg19: chr3-38650460;