rs794727444
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_001040142.2(SCN2A):c.5645G>A(p.Arg1882Gln) 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. R1882G) has been classified as 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 | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.5645G>A | p.Arg1882Gln | missense_variant | 27/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.5645G>A | p.Arg1882Gln | missense_variant | 27/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.5645G>A | p.Arg1882Gln | missense_variant | 27/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.5645G>A | p.Arg1882Gln | missense_variant | 27/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 11 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 19, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 15, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2017 | The R1882Q variant in the SCN2A has been reported multiple times previously as a de novo change in individuals with epileptic encephalopathy (Carvill et al., 2013; Howell et al., 2015; Trump et al., 2016). The R1882Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1882Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain, and missense variants at the same position (R1882G, R1882L) have been reported in the Human Gene Mutation Database in association with SCN2A-related disorders (Stenson et al., 2014). - |
Seizure Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Jun 24, 2024 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Apr 05, 2021 | - - |
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 | Apr 06, 2018 | Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-06 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight. - |
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 04, 2022 | This variant disrupts the p.Arg1882 amino acid residue in SCN2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26645390). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1882 of the SCN2A protein (p.Arg1882Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN2A-related conditions (PMID: 23708187, 29844171). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 196039). 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. Experimental studies have shown that this missense change affects SCN2A function (PMID: 29844171). For these reasons, this variant has been classified as Pathogenic. - |
Epileptic encephalopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
West syndrome;C0393706:Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Neurology Department, Shenzhen Children's Hospital | Feb 16, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at