rs74315392
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_172107.4(KCNQ2):c.740C>T(p.Ser247Leu) 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 29)
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 6.63
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
In a helix (size 24) 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;
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, 0.914
PP5
Variant 20-63442482-G-A is Pathogenic according to our data. Variant chr20-63442482-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205878.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=4}. Variant chr20-63442482-G-A is described in Lovd as [Pathogenic]. Variant chr20-63442482-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.740C>T | p.Ser247Leu | missense_variant | 5/17 | ENST00000359125.7 | NP_742105.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ2 | ENST00000359125.7 | c.740C>T | p.Ser247Leu | missense_variant | 5/17 | 1 | NM_172107.4 | ENSP00000352035 | A1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
29
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
29
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 04, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This substitution is predicted to be within the transmembrane segment S5; This variant is associated with the following publications: (PMID: 26633542, 34120799, 33897753, 30530441, 30552426, 31199083, 31628766, 32863083, 32770121, 33333793, 28252636, 33659638, 33811133, 35729264, 35217970, 35401395, 29314763) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 31, 2016 | - - |
Developmental and epileptic encephalopathy, 7 Pathogenic:2
| Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene, and are associated with developmental and epileptic encephalopathy 7 (MIM#613720) and benign neonatal seizures, 1 (MIM#121200), respectively (GeneReviews). There is currently no phenotypic correlation in terms of variant types or protein location (PMID: 31418850). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance however, this is only reported for patients with benign neonatal seizures (PMID: 25959266). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional pore domain in the fifth transmembrane region (PMID: 12742592, PMID: 33333793). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic in ClinVar, and de novo in multiple individuals with developmental and epileptic encephalopathy (DECIPHER, PMID: 33333793, PMID: 30552426). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 05, 2015 | - - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 25, 2023 | Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 32770121). 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: 205878). This missense change has been observed in individual(s) with KCNQ2-related conditions (PMID: 29314763, 32770121). 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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 247 of the KCNQ2 protein (p.Ser247Leu). This variant disrupts the p.Ser247 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12742592; Invitae). 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. - |
Seizures, benign familial neonatal, 1 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;D;D;D;T;D;D;.;.;.;.
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
PROVEAN
Pathogenic
.;.;.;.;D;.;D;.;D;D;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;.;.;.;D;.;D;.;D;D;D;.
Sift4G
Pathogenic
D;D;D;D;D;.;D;D;D;D;D;D
Polyphen
P;.;.;.;.;.;P;.;P;P;.;.
Vest4
MutPred
Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);.;Loss of catalytic residue at S247 (P = 0.0242);.;Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);Loss of catalytic residue at S247 (P = 0.0242);.;
MVP
MPC
1.9
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