rs796053203
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001040142.2(SCN2A):c.647T>G(p.Leu216Trp) 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. 11/17 in silico tools predict a damaging 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. L216S) 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.647T>G | p.Leu216Trp | missense_variant | 6/27 | ENST00000375437.7 | |
SCN2A | NM_001371246.1 | c.697+137T>G | intron_variant | ENST00000631182.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2A | ENST00000375437.7 | c.647T>G | p.Leu216Trp | missense_variant | 6/27 | 5 | NM_001040142.2 | P1 | |
SCN2A | ENST00000631182.3 | c.697+137T>G | intron_variant | 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 | Feb 14, 2022 | For these reasons, this variant has been classified as Pathogenic. 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"). ClinVar contains an entry for this variant (Variation ID: 207088). This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 30109124; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 216 of the SCN2A protein (p.Leu216Trp). - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2012 | The Leu216Trp missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Leu216Trp in approximately 5,000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Although both Leucine and Tryptophan are non-polar, Tryptophan is a larger residue with an aromatic side chain. The Leu216Trp substitution alters a highly conserved position in the S4 segment of the first transmembrane domain of the protein, and a different mutation in this same segment has been published in association with benign familial neonatal-infantile seizures (BFNIS) (Berkovic et al., 2004). Additionally, multiple in silico algorithms predict that Leu216Trp is damaging to protein structure/function. Therefore, Leu216Trp is a strong candidate for a disease-causing mutation, although the possibility that it is a benign variant cannot be excluded at present. The variant is found in INFANT-EPI panel(s). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at