rs752402332
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_Strong
The NM_014191.4(SCN8A):c.3008G>A(p.Arg1003His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging 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. R1003C) has been classified as Uncertain significance.
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.3008G>A | p.Arg1003His | missense_variant | 17/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.3008G>A | p.Arg1003His | missense_variant | 17/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.3008G>A | p.Arg1003His | missense_variant | 17/26 | ||
SCN8A | NM_001369788.1 | c.3008G>A | p.Arg1003His | missense_variant | 17/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.3008G>A | p.Arg1003His | missense_variant | 17/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.3008G>A | p.Arg1003His | missense_variant | 17/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248822Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134978
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461378Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726900
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 406258). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1003 of the SCN8A protein (p.Arg1003His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at