20-63442482-G-C
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_172107.4(KCNQ2):c.740C>G(p.Ser247Trp) variant causes a missense change. 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. S247L) has been classified as Pathogenic.
Frequency
Consequence
NM_172107.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 29
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 29
ClinVar
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
This missense change has been observed in individual(s) with clinical features of KCNQ2-related conditions (PMID: 12742592; Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 247 of the KCNQ2 protein (p.Ser247Trp). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 7389). 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 KCNQ2 protein function. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 12742592). This variant disrupts the p.Ser247 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29314763, 31199083). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect showing a reduction of the channel current (Dedek et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); This substitution is predicted to be within the transmembrane segment S5; This variant is associated with the following publications: (PMID: 19818940, 17129708, 19380078, 32770121, 12742592) -
Developmental and epileptic encephalopathy, 7 Pathogenic:1
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Seizures, benign familial neonatal, 2 Other:1
.Identified in a boy with EE (EE (epileptic encephalopathy); mother with BNE (benign neonatal epilepsy) (possible mosaicism; uncertain severity) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at