rs587777219

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):​c.794C>T​(p.Ala265Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A265T) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 29)

Consequence

KCNQ2
NM_172107.4 missense

Scores

11
6
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 9.77
Variant links:
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.

PM1
In a helix (size 11) in uniprot entity KCNQ2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_172107.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-63442429-C-T is described in Lovd as [Pathogenic].
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, 0.944
PP5
Variant 20-63442428-G-A is Pathogenic according to our data. Variant chr20-63442428-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63442428-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KCNQ2NM_172107.4 linkuse as main transcriptc.794C>T p.Ala265Val missense_variant 5/17 ENST00000359125.7 NP_742105.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KCNQ2ENST00000359125.7 linkuse as main transcriptc.794C>T p.Ala265Val missense_variant 5/171 NM_172107.4 ENSP00000352035 A1O43526-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 7 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneJun 26, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2013- -
Likely pathogenic, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesApr 27, 2019- -
not provided, no classification providedliterature onlyGeneReviews-EE (epileptic encephalopathy) -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalOct 01, 2021This sequence change in KCNQ2 is predicted to replace alanine with valine at codon 265 (p.(Ala265Val)). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the transmembrane ion transport domain in a region, amino acids 1-369, that is highly constrained. There is a moderate physicochemical difference between alanine and valine. This variant is absent from gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in 3 individuals and as a de novo occurrence with unconfirmed parental relationships in 2 individuals with Ohtahara syndrome or undetermined neonatal epileptic encephalopathy (NEE; PMID: 22926866, 23621294, 25959266, 32362866, 34354098). It has also been identified in 2 individuals with NEE and unknown de novo status (PMID: 25959266, 34395220). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict deleterious). Another missense variant c.793G>A, p.Ala265Thr in the same codon has been classified as pathogenic for NEE (ClinVar Variation ID: 197891). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_Strong, PM1, PM5, PS4_Supporting, PM2_Supporting. -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics Laboratory, Skane University Hospital LundFeb 14, 2024- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 09, 2022The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22926866, 23621294, 28867141, 30185235, 31036916, 31418850, 32362866, 32139178, 32917465, 33098118, 32712949, 31785789, 27602407) -
KCNQ2-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingMolecular Genetics Laboratory, BC Children's and BC Women's HospitalsJun 27, 2017- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMay 01, 2017The p.A265V variant (also known as c.794C>T), located in coding exon 5 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 794. The alanine at codon 265 is replaced by valine, an amino acid with similar properties. This variant as been observed de novo in unrelated patients with early onset epileptic encephalopathy (Saitsu H et al. Ann. Neurol., 2012 Aug;72:298-300; Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 25, 2023For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala265 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 23692823, 27535030, 27602407, 27779742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 120176). This missense change has been observed in individual(s) with early onset epileptic encephalopathy (PMID: 22926866, 30185235). 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 alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 265 of the KCNQ2 protein (p.Ala265Val). -
Intellectual disability Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Strasbourg University HospitalDec 01, 2017- -
Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCenter for Genomics, Ann and Robert H. Lurie Children's Hospital of ChicagoNov 11, 2021KCNQ2 NM_172107 exon 5 p.Ala265Val (c.794C>T): This variant has been reported in the literature in at least 2 individuals (1 with early onset epileptic encephalopathy and 1 with Ohtahara syndrome), both of whom were reported as de novo (Saitsu 2012 PMID:2292866, Kato 2013 PMID:23621294). This variant is not present in large control databases. This variant is present in ClinVar (Variation ID:120176). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this position (p.Ala265Thr, p.Ala265Pro) have been reported in association with disease, suggesting that this codon has functional significance. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. -
Seizure Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGénétique des Maladies du Développement, Hospices Civils de LyonJan 26, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
.;.;T;T;D;T;D;T;.;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.92
D
MutationAssessor
Uncertain
2.7
M;.;.;.;.;.;M;.;M;M;M;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.6
.;.;.;.;D;.;D;.;D;D;D;.
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
.;.;.;.;D;.;D;.;D;D;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D;D;.;D;D;D;D;D;D
Polyphen
0.78
P;.;.;.;.;.;P;.;P;P;.;.
Vest4
0.87
MutPred
0.76
Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);.;Loss of disorder (P = 0.0801);.;Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);Loss of disorder (P = 0.0801);.;
MVP
1.0
MPC
2.3
ClinPred
0.99
D
GERP RS
3.4
Varity_R
0.82
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587777219; hg19: chr20-62073781; COSMIC: COSV60431805; COSMIC: COSV60431805; API