rs1555870506
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_172107.4(KCNQ2):c.848del(p.Lys283SerfsTer36) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K283K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
NM_172107.4 frameshift
NM_172107.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.84
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 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-63439676-CT-C is Pathogenic according to our data. Variant chr20-63439676-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 530425.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.848del | p.Lys283SerfsTer36 | frameshift_variant | 6/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.848del | p.Lys283SerfsTer36 | frameshift_variant | 6/17 | 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:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2018 | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys283Serfs*36) in the KCNQ2 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with KCNQ2-related disease. Loss-of-function variants in KCNQ2 are known to be pathogenic (PMID: 14534157). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at