rs863224533
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001099404.2(SCN5A):c.4845_4847delinsGTA(p.Tyr1615_Phe1616delinsTer) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 30)
Consequence
SCN5A
NM_001099404.2 stop_gained
NM_001099404.2 stop_gained
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.31
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 143 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-38551525-AAG-TAC is Pathogenic according to our data. Variant chr3-38551525-AAG-TAC is described in ClinVar as [Pathogenic]. Clinvar id is 216142.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.4842_4844delinsGTA | p.Tyr1614_Phe1615delinsTer | stop_gained | 28/28 | ENST00000423572.7 | |
SCN5A | NM_001099404.2 | c.4845_4847delinsGTA | p.Tyr1615_Phe1616delinsTer | stop_gained | 28/28 | ENST00000413689.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.4845_4847delinsGTA | p.Tyr1615_Phe1616delinsTer | stop_gained | 28/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.4842_4844delinsGTA | p.Tyr1614_Phe1615delinsTer | stop_gained | 28/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Brugada syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2015 | This sequence change deletes 3 nucleotides and inserts 3 nucleotides in exon 28 of the SCN5A mRNA (c.4845_4847delCTCinsGTA), creating a premature translational stop signal at codon 1615 (p.Tyr1615*). It is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating mutations in SCN5A are known to be pathogenic (PMID: 19251209). Furthermore, another truncation variant at this position has been reported in an individual affected with Brugada syndrome (PMID: 20129283). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at