chr3-38633307-T-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001099404.2(SCN5A):c.1A>T(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SCN5A
NM_001099404.2 start_lost
NM_001099404.2 start_lost
Scores
8
3
3
Clinical Significance
Conservation
PhyloP100: 8.01
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
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-38633307-T-A is Pathogenic according to our data. Variant chr3-38633307-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520460.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1A>T | p.Met1? | start_lost | 2/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1A>T | p.Met1? | start_lost | 2/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1A>T | p.Met1? | start_lost | 2/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1A>T | p.Met1? | start_lost | 2/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Apr 18, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;.;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;.
Polyphen
B;P;.;B;.;P;P;.;.;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);Loss of MoRF binding (P = 0.0809);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at