rs1553181280
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_004974.4(KCNA2):c.1120A>G(p.Thr374Ala) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T374T) has been classified as Likely benign.
Frequency
Consequence
NM_004974.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNA2 | NM_004974.4 | c.1120A>G | p.Thr374Ala | missense_variant | 3/3 | ENST00000316361.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNA2 | ENST00000316361.10 | c.1120A>G | p.Thr374Ala | missense_variant | 3/3 | 2 | NM_004974.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 34
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 32 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects KCNA2 function (PMID: 29050392). 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 KCNA2 protein function. ClinVar contains an entry for this variant (Variation ID: 559647). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 27117551, 29050392). 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 threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 374 of the KCNA2 protein (p.Thr374Ala). - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | research | National Institute of Neuroscience, National Center of Neurology and Psychiatry | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Apr 23, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at