rs753829876
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_004974.4(KCNA2):āc.68A>Gā(p.Tyr23Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y23Y) has been classified as Likely benign.
Frequency
Consequence
NM_004974.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNA2 | NM_004974.4 | c.68A>G | p.Tyr23Cys | missense_variant | 3/3 | ENST00000316361.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNA2 | ENST00000316361.10 | c.68A>G | p.Tyr23Cys | missense_variant | 3/3 | 2 | NM_004974.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251440Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135892
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461878Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 32 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 23 of the KCNA2 protein (p.Tyr23Cys). This variant is present in population databases (rs753829876, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of KCNA2-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This missense change has been observed in at least one individual who was not affected with KCNA2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 476053). 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 not expected to disrupt KCNA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2019 | The p.Y23C variant (also known as c.68A>G), located in coding exon 1 of the KCNA2 gene, results from an A to G substitution at nucleotide position 68. The tyrosine at codon 23 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at