chr2-166039427-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP2PP3_StrongPP5
The NM_001165963.4(SCN1A):c.2585G>A(p.Arg862Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000279 in 1,434,906 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R862G) has been classified as Pathogenic.
Frequency
Consequence
NM_001165963.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN1A | NM_001165963.4 | c.2585G>A | p.Arg862Gln | missense_variant | 17/29 | ENST00000674923.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN1A | ENST00000674923.1 | c.2585G>A | p.Arg862Gln | missense_variant | 17/29 | NM_001165963.4 | P4 | ||
SCN1A-AS1 | ENST00000651574.1 | n.487+3297C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 145634Hom.: 0 Cov.: 31 FAILED QC
GnomAD4 exome AF: 0.00000279 AC: 4AN: 1434906Hom.: 0 Cov.: 36 AF XY: 0.00000140 AC XY: 1AN XY: 714540
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 145634Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 70430
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 23, 2020 | The frequency of this variant in the general population is consistent with pathogenicity. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. 2 de novo cases with parental identity not confirmed. - |
Severe myoclonic epilepsy in infancy Pathogenic:1Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Bioinformatics, Peking University | Dec 20, 2014 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 08, 2022 | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt SCN1A protein function. ClinVar contains an entry for this variant (Variation ID: 68593). This missense change has been observed in individual(s) with Dravet syndrome (PMID: 20110217, 21248271). In at least one individual the variant was observed to be de novo. 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 glutamine, which is neutral and polar, at codon 862 of the SCN1A protein (p.Arg862Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at