rs1057516094
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_172107.4(KCNQ2):c.802C>T(p.Leu268Phe) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L268P) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 29)
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
9
2
4
Clinical Significance
Conservation
PhyloP100: 6.74
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 16 ACMG points.
PM1
?
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chr20-63442419-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 219236.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
?
Missense variant where missense usually causes diseases, KCNQ2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.837
PP5
?
Variant 20-63442420-G-A is Pathogenic according to our data. Variant chr20-63442420-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 369763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.802C>T | p.Leu268Phe | missense_variant | 5/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.802C>T | p.Leu268Phe | missense_variant | 5/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 genomes
?
Cov.:
29
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 29
GnomAD4 genome
?
Cov.:
29
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu268 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27535030; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNQ2 protein function (PMID: 32179837). 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: 369763). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 25880994). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with phenylalanine at codon 268 of the KCNQ2 protein (p.Leu268Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. - |
Epileptic encephalopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Neurogenetics Laboratory - MEYER, AOU Meyer | Nov 16, 2016 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2021 | - - |
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
Uncertain
Eigen
Benign
Eigen_PC
Benign
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
Benign
L;.;.;.;.;.;L;.;L;L;L;.
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;T
Polyphen
P;.;.;.;.;.;P;.;P;P;.;.
Vest4
MutPred
Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);.;Loss of stability (P = 0.0748);.;Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);Loss of stability (P = 0.0748);.;
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