rs199473550

chr3-38633305-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_001099404.2(SCN5A):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN5A NM_001099404.2 start_lost
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.89

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_001099404.2 (SCN5A) was described as [Likely_pathogenic] in ClinVar as 520460
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.3G>A	p.Met1?	start_lost	2/28	ENST00000413689.6
SCN5A	NM_000335.5	c.3G>A	p.Met1?	start_lost	2/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.3G>A	p.Met1?	start_lost	2/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.3G>A	p.Met1?	start_lost	2/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Brugada syndrome Other:1

not provided, no classification provided

literature only

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

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This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20129283). 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;.;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;.
Polyphen		0.043	B;D;.;B;.;P;P;.;.;.;.
Vest4		0.96
MutPred		0.98		Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);Gain of catalytic residue at L6 (P = 0.0219);
MVP		0.96
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.82
gMVP		0.39

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: rs199473550; hg19: chr3-38674796;