rs527480102

Positions:

• chr3-38581026-C-G
• chr3-38581026-C-T

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.3133G>C​(p.Val1045Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN5A NM_000335.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.235

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]

SCN5A (HGNC:):

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 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 4.8279 (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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31669965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.3133G>C	p.Val1045Leu	missense_variant	17/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.3133G>C	p.Val1045Leu	missense_variant	17/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.3133G>C	p.Val1045Leu	missense_variant	17/28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.3133G>C	p.Val1045Leu	missense_variant	17/28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727110

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiac arrhythmia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This missense variant replaces valine with leucine at codon 1045 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SCN5A-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
CardioboostCm	Benign	0.0011
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;.;.;.;D;.;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.87	.;D;D;D;T;D;D;.;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.6	.;L;.;.;.;L;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T
Polyphen		0.12	B;P;.;B;.;B;B;.;.
Vest4		0.12
MutPred		0.49		Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);Gain of catalytic residue at V1045 (P = 0.0852);
MVP		0.86
MPC		0.039
ClinPred		0.56	D
GERP RS		3.3
Varity_R		0.28
gMVP		0.57

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: rs527480102; hg19: chr3-38622517;