rs863225046
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The NM_000334.4(SCN4A):c.4370G>A(p.Arg1457His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,611,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000334.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249256Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135116
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459498Hom.: 0 Cov.: 35 AF XY: 0.00000551 AC XY: 4AN XY: 725598
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
Congenital myasthenic syndrome 16 Pathogenic:1
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Hyperkalemic periodic paralysis Uncertain:1
This sequence change replaces arginine with histidine at codon 1457 of the SCN4A protein (p.Arg1457His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in the homozygous state in an individual affected with congenital myasthenic syndrome (PMID: 25707578). ClinVar contains an entry for this variant (Variation ID: 217263). This variant has been reported to affect SCN4A protein function (PMID: 25707578). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at