rs796053156
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5
The NM_001040142.2(SCN2A):c.4879G>A(p.Val1627Met) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1627A) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.4879G>A | p.Val1627Met | missense_variant | 27/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.4879G>A | p.Val1627Met | missense_variant | 27/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.4879G>A | p.Val1627Met | missense_variant | 27/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.4879G>A | p.Val1627Met | missense_variant | 27/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This variant is not present in population databases (gnomAD no frequency). 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 SCN2A protein function. ClinVar contains an entry for this variant (Variation ID: 207018). This missense change has been observed in individual(s) with epilepsy and SCN2A-related disorders (PMID: 28379373; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1627 of the SCN2A protein (p.Val1627Met). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2013 | p.Val1627Met (GTG>ATG): c.4879 G>A in exon 27 of the SCN2A gene (NM_021007.2). The Val627Met missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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. This variant is a conservative substitution, as Valine and Methionine are both uncharged, non-polar amino acids. It alters a highly conserved position in the S4 segment of the fourth transmembrane domain of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether Val627Met is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at