2-165389451-G-T
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_001040142.2(SCN2A):c.5645G>T(p.Arg1882Leu) 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 Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. 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 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.5645G>T | p.Arg1882Leu | missense_variant | Exon 27 of 27 | 5 | NM_001040142.2 | ENSP00000364586.2 | ||
SCN2A | ENST00000631182.3 | c.5645G>T | p.Arg1882Leu | missense_variant | Exon 27 of 27 | 5 | NM_001371246.1 | ENSP00000486885.1 | ||
SCN2A | ENST00000283256.10 | c.5645G>T | p.Arg1882Leu | missense_variant | Exon 27 of 27 | 1 | ENSP00000283256.6 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The R1882L variant in the SCN2A gene has been reported previously as a de novo variant in an individual with intractable epilepsy, intellectual disability, microcephaly, optic atrophy, and hypotonia (Baasch et al., 2014). Additionally different missense variants at the same position (R1882Q, R1882G) have been reported in association with SCN2A-related disorders (Carvill et al., 2013; Schwarz et al., 2016). The R1882L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1882L 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 occurs at a conserved position predicted to be within the C-terminal cytoplasmic domain of the protein, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the presence of R1882L is consistent with a diagnosis of a SCN2A-related disorder -
Complex neurodevelopmental disorder Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at