chr2-165386881-C-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001040142.2(SCN2A):c.4687C>G(p.Leu1563Val) variant causes a missense change involving the alteration of a non-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. L1563R) 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.4687C>G | p.Leu1563Val | missense_variant | 26/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.4687C>G | p.Leu1563Val | missense_variant | 26/27 | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.4687C>G | p.Leu1563Val | missense_variant | 26/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.4687C>G | p.Leu1563Val | missense_variant | 26/27 | 5 | NM_001371246.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
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 | Apr 13, 2022 | This missense change has been observed in individual(s) with benign familial neonatal-infantile seizures (PMID: 12243921). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1563 of the SCN2A protein (p.Leu1563Val). ClinVar contains an entry for this variant (Variation ID: 12877). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SCN2A function (PMID: 17021166, 17467289, 18479388). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 02, 2018 | The L1563V missense variant in the SCN2A gene has been previously reported to segregate withbenign familial neonatal-infantile seizures in large Ashkenazi Jewish family in Canada (Heron et al.,2002). Functional studies have demonstrated that L1563V causes a gain of channel function andincreases neuronal excitability in neonatal sodium channels (Misra, et al., 2008, Xu et al., 2007).This substitution alters a conserved position predicted to be in transmembrane segment S2 in thefourth homologous domain. The L1563V variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. - |
Seizures, benign familial infantile, 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 14, 2002 | - - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at