rs796053126
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001040142.2(SCN2A):c.2995G>A(p.Glu999Lys) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E999V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001040142.2 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 |
---|---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.2995G>A | p.Glu999Lys | missense_variant | 17/27 | ENST00000375437.7 | NP_001035232.1 | |
SCN2A | NM_001371246.1 | c.2995G>A | p.Glu999Lys | missense_variant | 17/27 | ENST00000631182.3 | NP_001358175.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.2995G>A | p.Glu999Lys | missense_variant | 17/27 | 5 | NM_001040142.2 | ENSP00000364586.2 | ||
SCN2A | ENST00000631182.3 | c.2995G>A | p.Glu999Lys | missense_variant | 17/27 | 5 | NM_001371246.1 | ENSP00000486885.1 | ||
SCN2A | ENST00000283256.10 | c.2995G>A | p.Glu999Lys | missense_variant | 17/27 | 1 | ENSP00000283256.6 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152102Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome Cov.: 32
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74424
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 11 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2020 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Complex neurodevelopmental disorder Pathogenic:1Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Pathogenic, no assertion criteria provided | provider interpretation | GenomeConnect - Simons Searchlight | Jul 14, 2016 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2016-07-14 and interpreted as Pathogenic. Variant was initially reported on 2015-07-31 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2023 | ClinVar contains an entry for this variant (Variation ID: 206981). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 23935176, 26648591, 26993267, 27867041, 28379373). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 999 of the SCN2A protein (p.Glu999Lys). 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 SCN2A protein function. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2017 | The E999K variant has been reported previously as a de novo variant in multiple individuals with Ohtahara syndrome, early infantile epileptic encephaopathy, and severe intellectual disability (Nakamura et al., 2013, Allen et al., 2015, Trump et al., 2016). The E999K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E999K 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 alters a conserved position in the intracellular loop between the second and third transmembrane domains (Shi et al., 2012), and other missense variants have been reported in this region of the protein in association with epilepsy. A missense change at the same codon (E999V) has been reported in association with SCN2A-related disorder (Stenson et al., 2014, Trump et al., 2016). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, E999K is considered a pathogenic variant. - |
Epilepsy of infancy with migrating focal seizures Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Neurology Department, Shenzhen Children's Hospital | Feb 16, 2022 | - - |
West syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Neurology Department, Shenzhen Children's Hospital | Feb 16, 2022 | - - |
Developmental and epileptic encephalopathy, 30 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Department of Neurology, Children’s Hospital of Chongqing Medical University | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at