chr12-51746002-A-G
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_001330260.2(SCN8A):c.2098A>G(p.Ile700Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. I700L) has been classified as Likely benign.
Frequency
Consequence
NM_001330260.2 missense
Scores
Clinical Significance
Conservation
Publications
- complex neurodevelopmental disorderInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- developmental and epileptic encephalopathy, 13Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- cognitive impairment with or without cerebellar ataxiaInheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
- seizures, benign familial infantile, 5Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- benign familial infantile epilepsyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- infantile convulsions and choreoathetosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- undetermined early-onset epileptic encephalopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- myoclonus, familial, 2Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN8A | NM_001330260.2 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 27 | ENST00000627620.5 | NP_001317189.1 | |
SCN8A | NM_014191.4 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 27 | ENST00000354534.11 | NP_055006.1 | |
SCN8A | NM_001177984.3 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 26 | NP_001171455.1 | ||
SCN8A | NM_001369788.1 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 26 | NP_001356717.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN8A | ENST00000354534.11 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 27 | 1 | NM_014191.4 | ENSP00000346534.4 | ||
SCN8A | ENST00000627620.5 | c.2098A>G | p.Ile700Val | missense_variant | Exon 13 of 27 | 5 | NM_001330260.2 | ENSP00000487583.2 | ||
SCN8A | ENST00000599343.5 | c.2131A>G | p.Ile711Val | missense_variant | Exon 12 of 26 | 5 | ENSP00000476447.3 | |||
SCN8A | ENST00000355133.7 | c.2098A>G | p.Ile700Val | missense_variant | Exon 12 of 25 | 1 | ENSP00000347255.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459256Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 725776 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy Uncertain:1
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. 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 not expected to disrupt SCN8A protein function. ClinVar contains an entry for this variant (Variation ID: 859199). This variant has not been reported in the literature in individuals affected with SCN8A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 700 of the SCN8A protein (p.Ile700Val). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at