rs199473270

Positions:

• chr3-38554512-T-C

Variant summary

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

The NM_001099404.2(SCN5A):​c.4580A>G​(p.Lys1527Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 5.10

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 repeat IV (size 297) in uniprot entity SCN5A_HUMAN there are 68 pathogenic changes around while only 2 benign (97%) in NM_001099404.2
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30492103).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4580A>G	p.Lys1527Arg	missense_variant	27/28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4577A>G	p.Lys1526Arg	missense_variant	27/28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4580A>G	p.Lys1527Arg	missense_variant	27/28	5	NM_001099404.2	ENSP00000410257	P4
SCN5A	ENST00000423572.7	c.4577A>G	p.Lys1526Arg	missense_variant	27/28	1	NM_000335.5	ENSP00000398266	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

-

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:15851320). 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
AlphaMissense	Benign	0.069
CardioboostCm	Benign	0.0064
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;.;.;.;.;T;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	.;T;T;T;T;T;T;.;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.1	.;.;.;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.24	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.57
Sift	Benign	0.62	T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T;T;T;T
Polyphen		0.012	B;B;.;B;.;B;B;.;.
Vest4		0.45
MutPred		0.38		.;.;Loss of methylation at K1527 (P = 0.0022);.;.;Loss of methylation at K1527 (P = 0.0022);.;.;.;
MVP		0.93
MPC		0.42
ClinPred		0.78	D
GERP RS		3.7
Varity_R		0.48
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199473270; hg19: chr3-38596003;