2-166012276-C-G
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate
The NM_001165963.4(SCN1A):c.3712G>C(p.Glu1238Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E1238D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001165963.4 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 |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.3712G>C | p.Glu1238Gln | missense_variant | 22/29 | ENST00000674923.1 | |
LOC102724058 | NR_110598.1 | n.176-3337C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.3712G>C | p.Glu1238Gln | missense_variant | 22/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.193-3337C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246472Hom.: 0 AF XY: 0.00000750 AC XY: 1AN XY: 133388
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1454194Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2AN XY: 723564
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 07, 2020 | In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is in the extracellular loop between segments 1 & 2 of the D3 domain in SCN1A, at a glutamic acid residue that is highly conserved across ion channel genes (PMID: 18804930, 22581653). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs750364705, ExAC 0.01%) but has not been reported in the literature in individuals with a SCN1A-related disease. A different variant at this codon, c.3714A>C (p.Glu1238Asp), and two variants at the adjacent codon, c.3715G>T (p.D1239Y) and c.3716A>G (p.D1239G), have all been seen in individuals affected with epilepsy (PMID: 16713920, 17347258, 18930999), however the clinical significance of these variants is unknown. This sequence change replaces glutamic acid with glutamine at codon 1238 of the SCN1A protein (p.Glu1238Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at