rs879255709
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001330260.2(SCN8A):c.4948G>A(p.Ala1650Thr) 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. A1650V) has been classified as Pathogenic.
Frequency
Consequence
NM_001330260.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.4948G>A | p.Ala1650Thr | missense_variant | 27/27 | ENST00000627620.5 | NP_001317189.1 | |
SCN8A | NM_014191.4 | c.4948G>A | p.Ala1650Thr | missense_variant | 27/27 | ENST00000354534.11 | NP_055006.1 | |
SCN8A | NM_001177984.3 | c.4825G>A | p.Ala1609Thr | missense_variant | 26/26 | NP_001171455.1 | ||
SCN8A | NM_001369788.1 | c.4825G>A | p.Ala1609Thr | missense_variant | 26/26 | NP_001356717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.4948G>A | p.Ala1650Thr | missense_variant | 27/27 | 1 | NM_014191.4 | ENSP00000346534.4 | ||
SCN8A | ENST00000627620.5 | c.4948G>A | p.Ala1650Thr | missense_variant | 27/27 | 5 | NM_001330260.2 | ENSP00000487583.2 | ||
SCN8A | ENST00000599343.5 | c.4981G>A | p.Ala1661Thr | missense_variant | 26/26 | 5 | ENSP00000476447.3 | |||
SCN8A | ENST00000355133.7 | c.4825G>A | p.Ala1609Thr | missense_variant | 25/25 | 1 | ENSP00000347255.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2016 | The A1650T pathogenic variant in the SCN8A gene has been reported previously as a de novo variant in two unrelated individuals whose combined features include intractable early-onset epileptic encephalopathy, severely regressed development, intellectual disability, quadriparesis with dystonic posturing, hypotonia, and MRI abnormalities including asymmetric ventricles and mild diffuse atrophy (Larsen et al., 2015; Ohba et al., 2014). The A1650T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1650T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A1650T as a pathogenic variant. - |
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