3-38581032-C-G

Variant names:

• chr3-38581032-C-G
• rs1318798411
• NM_001099404.2:c.3127G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000335.5(SCN5A):​c.3127G>C​(p.Glu1043Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

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 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 267) in uniprot entity SCN5A_HUMAN there are 26 pathogenic changes around while only 11 benign (70%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SCN5A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 99 curated pathogenic missense variants (we use a threshold of 10). The gene has 60 curated benign missense variants. Gene score misZ: 2.7504 (below the threshold of 3.09). Trascript score misZ: 4.8279 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3096236).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3127G>C	p.Glu1043Gln	missense_variant	Exon 17 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3127G>C	p.Glu1043Gln	missense_variant	Exon 17 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3127G>C	p.Glu1043Gln	missense_variant	Exon 17 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3127G>C	p.Glu1043Gln	missense_variant	Exon 17 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 463319). This variant has not been reported in the literature in individuals affected with SCN5A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1043 of the SCN5A protein (p.Glu1043Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
CardioboostCm	Benign	0.0033
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;.;.;.;T;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Benign	1.4	.;L;.;.;.;L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.22	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T;T;T
Polyphen		0.78	P;P;.;P;.;P;P;.;.
Vest4		0.23
MutPred		0.41		Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);Loss of catalytic residue at E1043 (P = 0.0977);
MVP		0.28
MPC		0.14
ClinPred		0.77	D
GERP RS		5.1
Varity_R		0.15
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: rs1318798411; hg19: chr3-38622523;