chr20-63439644-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_ModeratePM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The ENST00000359125.7(KCNQ2):c.881C>T(p.Ala294Val) 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A294G) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
ENST00000359125.7 missense
ENST00000359125.7 missense
Scores
9
8
2
Clinical Significance
Conservation
PhyloP100: 6.48
Genes affected
KCNQ2 (HGNC:6296): (potassium voltage-gated channel subfamily Q member 2) The M channel is a slowly activating and deactivating potassium channel that plays a critical role in the regulation of neuronal excitability. The M channel is formed by the association of the protein encoded by this gene and a related protein encoded by the KCNQ3 gene, both integral membrane proteins. M channel currents are inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. Defects in this gene are a cause of benign familial neonatal convulsions type 1 (BFNC), also known as epilepsy, benign neonatal type 1 (EBN1). At least five transcript variants encoding five different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PS1
Transcript ENST00000359125.7 (KCNQ2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000359125.7
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-63439644-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 3254540.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ 4.0411 (greater than the threshold 3.09). Trascript score misZ 3.6968 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915
PP5
Variant 20-63439644-G-A is Pathogenic according to our data. Variant chr20-63439644-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 205886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439644-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KCNQ2 | NM_172107.4 | c.881C>T | p.Ala294Val | missense_variant | 6/17 | ENST00000359125.7 | NP_742105.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ2 | ENST00000359125.7 | c.881C>T | p.Ala294Val | missense_variant | 6/17 | 1 | NM_172107.4 | ENSP00000352035 | A1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 7 Pathogenic:5Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan | Apr 18, 2022 | PS3, PS4, PP3 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant p.A294V in KCNQ2 (NM_172107.3) has been previously reported as a de novo variant in multiple affected individuals with early onset epileptic encephalopathy (Pisano et al, 2015; Allen et al, 2014; Epi4K Consortium et al, 2013). Functional studies indicate that variant alters protein expression and function (Abidi et al, 2015). The variant has been submitted to ClinVar as a Pathogenic variant. The p.A294V variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.A294V missense variant is predicted to be damaging by both SIFT and PolyPhen2. The alanine residue at codon 294 of KCNQ2 is conserved in all mammalian species. The nucleotide c.881 in KCNQ2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic - |
| Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Aug 19, 2022 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
| Pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Nov 02, 2017 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 28, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2018 | The A294V variant in the KCNQ2 gene has been reported previously as a de novo pathogenic variant in multiple unrelated individuals with early-onset epileptic encephalopathy (Milh et al., 2013; Kato et al., 2013, Allen et al., 2014). Additionally, the A294V variant has been observed as a de novo variant with confirmed parentage in a patient previously tested at GeneDx, and has been reported as a de novo variant in patients reported in other databases including ClinVar and LOVD. Functional studies of A294V indicate that the variant alters protein expression and function (Abidi et al., 2015). The A294V variant is not observed in large population cohorts (Lek et al., 2016). The A294V variant is a conservative amino acid substitution; however, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different pathogenic missense variant at the same position (A294G) and other variants nearby residues have been reported in individuals with KCNQ2-related disorders (Steinlein et al., 2007; Stenson et al., 2014). Therefore, the presence of A294V is consistent with the diagnosis of a KCNQ2-related disorder in this individual. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 02, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2017 | - - |
KCNQ2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Dec 20, 2019 | This variant has been previously reported as a de novo change in multiple unrelated individuals with early-onset epileptic encephalopathy (PMID: 23692823, 23621294, 25052858). Functional studies indicate that this variant alters subcellular localization of the encoded potassium channel (PMID: 26007637). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.881C>T (p.Ala294Val) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.881C>T (p.Ala294Val) variant is classified as Pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 294 of the KCNQ2 protein (p.Ala294Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset epileptic encephalopathy (PMID: 23692823, 25052858, 25880994, 26007637, 27602407). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205886). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 26007637, 27905566). For these reasons, this variant has been classified as Pathogenic. - |
Seizures, benign familial neonatal, 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Sep 08, 2002 | - - |
Epileptic encephalopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
Seizure Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Jun 16, 2024 | - - |
Complex neurodevelopmental disorder Other:1
| not provided, no classification provided | literature only | Channelopathy-Associated Epilepsy Research Center | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;.;T;T;D;T;D;T;.;.;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;H;.;H;H;H
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
.;.;.;.;D;.;D;.;D;D;D
REVEL
Pathogenic
Sift
Uncertain
.;.;.;.;D;.;D;.;D;D;D
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.
Vest4
MutPred
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
MPC
2.6
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at