rs267607198
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_172107.4(KCNQ2):c.1662G>T(p.Lys554Asn) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K554K) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
NM_172107.4 missense
NM_172107.4 missense
Scores
7
6
1
Clinical Significance
Conservation
PhyloP100: 2.65
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 11 ACMG points.
PM1
?
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_172107.4
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, KCNQ2
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.958
PP5
?
Variant 20-63413551-C-A is Pathogenic according to our data. Variant chr20-63413551-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7388.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ2 | NM_172107.4 | c.1662G>T | p.Lys554Asn | missense_variant | 15/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.1662G>T | p.Lys554Asn | missense_variant | 15/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Seizures, benign familial neonatal, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 13, 2004 | - - |
Seizures, benign familial neonatal, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Mar 31, 2016 | Uncertain severity. 2/4 therapy-resistant seizures and intellectual disability. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | KCNQ2: PS3, PM2, PS4:Moderate, PP2, PP3, PP4 - |
Developmental and epileptic encephalopathy, 7 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 13, 2004 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
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
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.
Vest4
MutPred
0.86
.;.;.;.;.;.;Loss of methylation at K554 (P = 0.0085);.;.;.;.;
MVP
MPC
1.7
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