rs199473136

chr3-38599026-C-Gchr3-38599026-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001099404.2(SCN5A):c.1915G>C(p.Gly639Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. G639G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 2.12

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• BP4: Computational evidence support a benign effect (MetaRNN=0.2837165).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1915G>C	p.Gly639Arg	missense_variant	13/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1915G>C	p.Gly639Arg	missense_variant	13/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1915G>C	p.Gly639Arg	missense_variant	13/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1915G>C	p.Gly639Arg	missense_variant	13/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246566 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456168 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16922724). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
CardioboostArm	Benign	0.000094
CardioboostCm	Benign	0.015
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	16
Dann	Benign	0.88
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	0.80	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.7	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.79	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;B;B;.;.
Vest4		0.89
MutPred		0.68		Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);Gain of glycosylation at P637 (P = 0.1215);
MVP		0.81
MPC		0.42
ClinPred		0.16	T
GERP RS		1.9
Varity_R		0.036
gMVP		0.55

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: rs199473136; hg19: chr3-38640517;