rs199473064

chr3-38620926-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_001099404.2(SCN5A):c.528T>G(p.Ile176Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SCN5A NM_001099404.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: -0.961

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a helix (size 21) in uniprot entity SCN5A_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_001099404.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCN5A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN5A	NM_001099404.2	c.528T>G	p.Ile176Met	missense_variant	5/28	ENST00000413689.6
SCN5A	NM_000335.5	c.528T>G	p.Ile176Met	missense_variant	5/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.528T>G	p.Ile176Met	missense_variant	5/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.528T>G	p.Ile176Met	missense_variant	5/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461582 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727046

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Congenital long QT 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 Long QT syndrome in the following publications (PMID:19996378). 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	0.26
CardioboostArm	Uncertain	0.31
CardioboostCm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	0.84	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.028	D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.039	D;D;D;D;D;D;D;D;D;T
Polyphen		1.0	D;D;.;D;.;D;D;.;.;.
Vest4		0.97
MutPred		0.92		Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);Loss of ubiquitination at K175 (P = 0.0709);
MVP		0.97
MPC		1.1
ClinPred		0.98	D
GERP RS		-5.0
Varity_R		0.66
gMVP		0.94

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: rs199473064; hg19: chr3-38662417;