rs118047588
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBS1_Supporting
The NM_000334.4(SCN4A):c.4222C>T(p.Arg1408Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 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. R1408S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN4A | NM_000334.4 | c.4222C>T | p.Arg1408Cys | missense_variant | 23/24 | ENST00000435607.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN4A | ENST00000435607.3 | c.4222C>T | p.Arg1408Cys | missense_variant | 23/24 | 1 | NM_000334.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000545 AC: 83AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000184 AC: 46AN: 250326Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 135492
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461690Hom.: 1 Cov.: 32 AF XY: 0.0000440 AC XY: 32AN XY: 727130
GnomAD4 genome ? AF: 0.000558 AC: 85AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45AN XY: 74502
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 06, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2023 | Reported in one affected individual from a case-control study of atrioventricular nodal re-entry tachycardia; however, specific phenotype information was not provided (Luo et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32508047) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 29, 2020 | - - |
Hyperkalemic periodic paralysis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1408 of the SCN4A protein (p.Arg1408Cys). This variant is present in population databases (rs118047588, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SCN4A-related conditions. ClinVar contains an entry for this variant (Variation ID: 568015). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN4A protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Paramyotonia congenita of Von Eulenburg;C0238357:Hyperkalemic periodic paralysis;C2750061:Hypokalemic periodic paralysis, type 2;C2931826:Potassium-aggravated myotonia;C3280112:Congenital myasthenic syndrome 16;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at