chr3-38630330-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP2
The NM_001099404.2(SCN5A):c.373G>A(p.Val125Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V125L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SCN5A
NM_001099404.2 missense
NM_001099404.2 missense
Scores
2
12
4
Clinical Significance
Conservation
PhyloP100: 3.95
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a helix (size 7) in uniprot entity SCN5A_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001099404.2
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr3-38630330-C-G is described in Lovd as [Pathogenic].
PP2
?
Missense variant where missense usually causes diseases, SCN5A
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.373G>A | p.Val125Met | missense_variant | 3/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.373G>A | p.Val125Met | missense_variant | 3/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.373G>A | p.Val125Met | missense_variant | 3/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.373G>A | p.Val125Met | missense_variant | 3/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460590Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726730
GnomAD4 exome
AF:
AC:
1
AN:
1460590
Hom.:
Cov.:
29
AF XY:
AC XY:
0
AN XY:
726730
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cardiac arrhythmia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 08, 2020 | This missense variant replaces valine with methionine at codon 125 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostArm
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
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
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;.
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D
Polyphen
P;D;.;P;.;P;P;.;.;.
Vest4
MutPred
Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);Loss of methylation at K126 (P = 0.0201);
MVP
MPC
1.1
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