3-38599028-C-T

Position:

• chr3-38599028-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001099404.2(SCN5A):​c.1913G>A​(p.Gly638Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G638G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 1.51

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN5A. . Gene score misZ 2.7504 (greater than the threshold 3.09). Trascript score misZ 4.7729 (greater than threshold 3.09). GenCC has associacion of gene with progressive familial heart block, type 1A, Brugada syndrome, familial sick sinus syndrome, short QT syndrome, paroxysmal familial ventricular fibrillation, progressive familial heart block, long QT syndrome 3, familial atrial fibrillation, catecholaminergic polymorphic ventricular tachycardia, dilated cardiomyopathy, dilated cardiomyopathy 1E, arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome 1, atrial standstill, familial isolated dilated cardiomyopathy, familial long QT syndrome, sick sinus syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1913G>A	p.Gly638Asp	missense_variant	13/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1913G>A	p.Gly638Asp	missense_variant	13/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1913G>A	p.Gly638Asp	missense_variant	13/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1913G>A	p.Gly638Asp	missense_variant	13/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456016 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 723002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 638 of the SCN5A protein (p.Gly638Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. ClinVar contains an entry for this variant (Variation ID: 67697). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:19841300;PMID:20129283). -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Aug 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
CardioboostCm	Benign	0.0054
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;.;.;.;.;D;.;.;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;.;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.2	.;L;.;.;.;L;.;.;.
MutationTaster	Benign	0.57	D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.40	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;T;T;T;T
Polyphen		0.86	P;B;.;P;.;P;P;.;.
Vest4		0.29
MutPred		0.30		Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);
MVP		0.92
MPC		0.57
ClinPred		0.46	T
GERP RS		4.2
Varity_R		0.077
gMVP		0.58

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: rs199473578; hg19: chr3-38640519;