3-38622401-C-G

Variant names:

• chr3-38622401-C-G
• rs199473062
• NM_001099404.2:c.481G>C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000335.5(SCN5A):​c.481G>C​(p.Glu161Gln) variant causes a missense, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E161K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_000335.5 missense, splice_region
• Scores: Splicing: ADA: 0.9127
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.90

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 11 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S2 of repeat I (size 20) in uniprot entity SCN5A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-38622401-C-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.481G>C	p.Glu161Gln	missense_variant, splice_region_variant	Exon 4 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.481G>C	p.Glu161Gln	missense_variant, splice_region_variant	Exon 4 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.481G>C	p.Glu161Gln	missense_variant, splice_region_variant	Exon 4 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.481G>C	p.Glu161Gln	missense_variant, splice_region_variant	Exon 4 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Brugada syndrome Other:1

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.045	D;D;D;D;D;D;D;D;D;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.;.
Vest4		0.98
MutPred		0.90		Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);Gain of ubiquitination at K158 (P = 0.078);
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.78
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.11		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: rs199473062; hg19: chr3-38663892;