rs794728941

chr3-38550387-G-Cchr3-38550387-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001099404.2(SCN5A):c.5985C>G(p.Tyr1995Ter) variant causes a stop gained change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_001099404.2 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.271

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 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• 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.5985C>G	p.Tyr1995Ter	stop_gained	28/28	ENST00000413689.6
SCN5A	NM_000335.5	c.5982C>G	p.Tyr1994Ter	stop_gained	28/28	ENST00000423572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN5A	ENST00000413689.6	c.5985C>G	p.Tyr1995Ter	stop_gained	28/28	5	NM_001099404.2	P4
SCN5A	ENST00000423572.7	c.5982C>G	p.Tyr1994Ter	stop_gained	28/28	1	NM_000335.5	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2016

The Y1995S variant has not been published as a pathogenic variant or as a benign variant to ourknowledge. This nonsense variant may cause loss of normal protein function through proteintruncation but is not expected to result in nonsense-mediated mRNA decay. The Y1995S variant wasnot observed in approximately 6,500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.However, a control cohort of individuals from Saudi Arabia is not available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.024
FATHMM_MKL	Benign	0.51	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
Vest4		0.78
GERP RS		2.2

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: rs794728941; hg19: chr3-38591878;