20-63438645-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP2PP3_ModeratePP5_Moderate
The NM_172107.4(KCNQ2):c.1003C>G(p.Pro335Ala) 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. P335L) has been classified as Pathogenic.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro335 amino acid residue in KCNQ2. Another variant that disrupts this residue has been observed in affected individuals (Invitae, PMID: 28867141), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with early infantile epileptic encephalopathy (PMID: Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 335 of the KCNQ2 protein (p.Pro335Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at