3-38603780-C-T

Position:

• chr3-38603780-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001099404.2(SCN5A):​c.1822G>A​(p.Asp608Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,405,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.828

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 1 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=0.1323457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.1822G>A	p.Asp608Asn	missense_variant	12/28	ENST00000413689.6
SCN5A	NM_000335.5	c.1822G>A	p.Asp608Asn	missense_variant	12/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.1822G>A	p.Asp608Asn	missense_variant	12/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.1822G>A	p.Asp608Asn	missense_variant	12/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000929 AC: 2 AN: 215216 Hom.: 0 AF XY: 0.00000869 AC XY: 1 AN XY: 115086

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: 0.0000455

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000100

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 26 AN: 1405158 Hom.: 0 Cov.: 30 AF XY: 0.0000174 AC XY: 12 AN XY: 690910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000129

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 608 of the SCN5A protein (p.Asp608Asn). This variant is present in population databases (rs755114387, gnomAD 0.005%). 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: 570937). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Cardiac arrhythmia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 07, 2022	This missense variant replaces aspartic acid with asparagine at codon 608 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 2/215216 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 23, 2023	This missense variant replaces aspartic acid with asparagine at codon 608 of the SCN5A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 been identified in 2/215216 chromosomes 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	0.086
CardioboostCm	Benign	0.0043
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Uncertain	1.0
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.094	N
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.28	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T;T
Polyphen		0.0020	B;B;.;B;.;P;B;.;.
Vest4		0.096
MutPred		0.19		Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);Loss of solvent accessibility (P = 0.1202);
MVP		0.40
MPC		0.37
ClinPred		0.090	T
GERP RS		4.2
Varity_R		0.049
gMVP		0.65

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: rs755114387; hg19: chr3-38645271; COSMIC: COSV61119914;