rs796053178
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001040142.2(SCN2A):c.1147C>G(p.Gln383Glu) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Q383L) 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 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2A | NM_001040142.2 | c.1147C>G | p.Gln383Glu | missense_variant | 9/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.1147C>G | p.Gln383Glu | missense_variant | 9/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.1147C>G | p.Gln383Glu | missense_variant | 9/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.1147C>G | p.Gln383Glu | missense_variant | 9/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
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 | Jun 16, 2017 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in the literature in an individual with Ohtahara syndrome and a sibling affected with benign familial neonatal-infantile seizures inherited from an obligate carrier father affected with infantile epilepsy and intellectual disability (PMID: 27781028). In addition, family studies have indicated that this variant was not present in the parents of an individual with early-onset epilepsy, which suggests that it was de novo in that affected individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 207050). This variant is not present in population databases (rs796053178, ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 383 of the SCN2A protein (p.Gln383Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 14, 2013 | p.Gln383Glu (CAA>GAA): c.1147 C>G in exon 9 of the SCN2A gene (NM_021007.2). The Gln383Glu 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 or among the various ethnic groups studied in the 1000 Genomes Project, indicating it is not a common benign variant in these populations. The amino acid substitution is non-conservative as an uncharged Glutamine residue is replaced by a negatively charged Glutamic acid residue. Gln383Glu alters a conserved position between the S5 and S6 segments of the first transmembrane domain of the protein and several in-silico algorithms predict it may be damaging to the structure/function of the protein. This variant has been observed de novo without verified parentage. The variant is found in EPILEPSY panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at