rs727503974
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_172107.4(KCNQ2):c.821C>T(p.Thr274Met) 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T274S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_172107.4 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 |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.821C>T | p.Thr274Met | missense_variant | 6/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.821C>T | p.Thr274Met | missense_variant | 6/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 7 Pathogenic:6Other:1
Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Aug 19, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center of Genomic medicine, Geneva, University Hospital of Geneva | Aug 11, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Mar 19, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | The variant has been previously reported as de novo in a similarly affected individual (PMID: 22275249, 27535030, PS2_S). It has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 22275249, 27535030, 27779742, 28133863, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24318194, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94, PP3_P). A missense variant is a common mechanism associated with Epileptic encephalopathy (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 18, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 28, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2023 | Published functional studies demonstrate a damaging effect, as current amplitudes of homotetramers and heterotetramers were reduced (Orhan et al., 2014); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22275249, 29056246, 28133863, 27779742, 31273778, 20437616, 27602407, 23692823, 25960349, 28488083, 30776697, 27535030, 31780880, 33041849, 32239694, 33822359, 34055682, 33098118, 31175295, 31440721, 35217970, 24318194) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 25, 2019 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 24318194). 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. ClinVar contains an entry for this variant (Variation ID: 167208). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 22275249, 27535030, 27779742, 28133863). 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 methionine, which is neutral and non-polar, at codon 274 of the KCNQ2 protein (p.Thr274Met). - |
Seizures, benign familial neonatal, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Sep 08, 2002 | - - |
West syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Dec 15, 2023 | - - |
Complex neurodevelopmental disorder Other:1
not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at