rs118192200
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_172107.4(KCNQ2):c.620G>A(p.Arg207Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,256 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207W) 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.620G>A | p.Arg207Gln | missense_variant | 4/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.620G>A | p.Arg207Gln | missense_variant | 4/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1451256Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1AN XY: 720834
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 31, 2022 | Previously reported in an individual with myokymia due to peripheral nerve hyperexcitability, and functional studies indicate this variant alters voltage-dependent activation (Wuttke et al., 2007; Miceli et al., 2012); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17872363, 29655203, 22455920, 32184343, 25959266, 25741868, 24375629, 22169383, 11572947, 32884139, 32506321, 33098118) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 08, 2019 | Not found in the total gnomAD dataset, and the data is high quality (0/270462 chr). Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 18, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the KCNQ2 protein (p.Arg207Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 17872363, 25959266, 29655203, 32184343, 34711204). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7391). 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: 17872363, 22455920). This variant disrupts the p.Arg207 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11572947, 22169383, 22455920, 24375629). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Seizures, benign familial neonatal, 1, and/or myokymia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 27, 2007 | - - |
Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Developmental and epileptic encephalopathy, 7 Other:1
not provided, no classification provided | literature only | GeneReviews | - | Myokymia, EE (epileptic encephalopathy) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at