rs118192215
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_172107.4(KCNQ2):c.997C>T(p.Arg333Trp) 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. R333Q) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
10
4
1
Clinical Significance
Conservation
PhyloP100: 3.74
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 hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr20-63438650-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, KCNQ2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
Variant 20-63438651-G-A is Pathogenic according to our data. Variant chr20-63438651-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 21809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63438651-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.997C>T | p.Arg333Trp | missense_variant | 7/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.997C>T | p.Arg333Trp | missense_variant | 7/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461482Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727020
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1461482
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Cov.:
31
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AC XY:
0
AN XY:
727020
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2021 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27602407, 32593896, 20437616, 30182498, 28191890, 28135719, 28867141, 16039833, 23692823, 23621294) - |
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 | - | The c.997C>T (p.Arg333Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a de novo and heterozygous change in patients with early onset epileptic encephalopathies (PMID: 16039833, 23621294, 23692823, 30182498, 31440721, 32593896). The c.997C>T (p.Arg333Trp) variant is located in a mutational hotspot for pathogenic variations associated with KCNQ2-related disorders (PMID: 30008368). A different amino acid change at the same residue, KCNQ2 c.998G>A (p.Arg333Gln), has been previously reported in individuals with benign neonatal seizures (PMID: 14534157, 29215089, 31152295, 31832524, 33897753). Functional studies indicate that the p.Arg333Trp variant reduced axonal surface expression of potassium voltage-gated channels, reduced the sensitivity of the channels to phosphatidylinositol-4,5-bisphosphate (PIP2) stimulation, and disrupted the ability to inhibit excitability in hippocampal neurons (PMID: 30008368). The c.997C>T (p.Arg333Trp) variant is absent from the gnomAD population database and thus is presumed to be rare. 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, c.997C>T (p.Arg333Trp) is classified as Pathogenic. - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 333 of the KCNQ2 protein (p.Arg333Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal seizures (PMID: 16039833, 23621294, 23692823). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 21809). 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%. For these reasons, this variant has been classified as Pathogenic. - |
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 | - | EE (epileptic encephalopathy) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
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
Uncertain
M;.;.;.;.;.;M;.;M;M;M
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.
Vest4
MutPred
Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);.;Loss of disorder (P = 0.005);.;Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);Loss of disorder (P = 0.005);
MVP
MPC
2.8
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