rs796052623
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP2PP3_StrongPP5
The NM_172107.4(KCNQ2):c.601C>T(p.Arg201Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R201H) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
11
3
1
Clinical Significance
Conservation
PhyloP100: 1.17
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 10 ACMG points.
PM1
?
In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_172107.4
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr20-63444747-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 369753.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, 0.985
PP5
?
Variant 20-63444748-G-A is Pathogenic according to our data. Variant chr20-63444748-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205869.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=10, not_provided=2, Uncertain_significance=1}. Variant chr20-63444748-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.601C>T | p.Arg201Cys | missense_variant | 4/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.601C>T | p.Arg201Cys | missense_variant | 4/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1453118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 721920
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1453118
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Cov.:
32
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AC XY:
0
AN XY:
721920
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:1Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 7 Pathogenic:7Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.601C>T (p.Arg201Cys) in the KCNQ2 gene has been reported in heterozygous state in an individual affected with early onset epileptic encephalopathy (Hortigüela M. et al., 2017). Experimental studies have shown that this missense change stabilized the activated state of the channel, thereby producing gain-of function (Miceli F. et al., 2015). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes databases. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Uncertain Significance. The amino acid Arginine at position 201 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000205869, PMID:24107868). The variant has been previously reported as de novo in a similarly affected individual (PMID: 27535030). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000369753, PMID:23708187). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.931>=0.6, 3CNET: 0.997>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. TTherefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
Pathogenic, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Pathogenic, for Epileptic encephalopathy, early infantile, 7, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect. Loss of voltage-dependent channel gating and increased channel activation, gain-of-function mutation (PMID:25740509). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:26993267,28133863,24107868,28687180). PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:28687180). - |
Pathogenic, criteria provided, single submitter | clinical testing | NeuroMeGen, Hospital Clinico Santiago de Compostela | - | - - |
Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Aug 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
Seizures, benign familial neonatal, 1 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Sep 08, 2002 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | Likely pathogenicity based on finding it once in our laboratory de novo in a 6-month-old female with motor delays, hypotonia, epilepsy (clinically thought to be early infantile myoclonic encephalopathy, onset at day 2 of life, with apneic episodes, controlled by medication but with onset of myoclous), nystagmus - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2021 | Published functional studies demonstrate a gain-of-function (Miceli et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 28687180, 25740509, 27535030, 28133863, 28867141, 24107868, 28139826, 32917465) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the KCNQ2 protein (p.Arg201Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early infantile epileptic encephalopathy (PMID: 24107868, 27535030, 28133863, 28687180). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 205869). 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: 25740509). This variant disrupts the p.Arg201 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23708187, 25880994, 28139826, 29190809). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 | - | - - |
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;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;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
Pathogenic
D
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);.;Loss of MoRF binding (P = 0.0037);.;Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);Loss of MoRF binding (P = 0.0037);.;
MVP
MPC
3.3
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