12-51699642-T-C
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_014191.4(SCN8A):c.779T>C(p.Phe260Ser) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F260V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014191.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.779T>C | p.Phe260Ser | missense_variant | 7/27 | ENST00000627620.5 | |
SCN8A | NM_014191.4 | c.779T>C | p.Phe260Ser | missense_variant | 7/27 | ENST00000354534.11 | |
SCN8A | NM_001177984.3 | c.779T>C | p.Phe260Ser | missense_variant | 7/26 | ||
SCN8A | NM_001369788.1 | c.779T>C | p.Phe260Ser | missense_variant | 7/26 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.779T>C | p.Phe260Ser | missense_variant | 7/27 | 1 | NM_014191.4 | P4 | |
SCN8A | ENST00000627620.5 | c.779T>C | p.Phe260Ser | missense_variant | 7/27 | 5 | NM_001330260.2 | A1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2020 | For these reasons, this variant has been classified as Pathogenic. 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"). This variant has been observed in individual(s) with clinical features of early infantile epileptic encephalopathy (PMID: 25568300, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 253279). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 260 of the SCN8A protein (p.Phe260Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. - |
Developmental and epileptic encephalopathy, 13 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at