rs1060500603
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_172107.4(KCNQ2):c.2179_2180insCGCCAGG(p.Gly727AlafsTer140) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G727G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
NM_172107.4 frameshift
NM_172107.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.492
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-63407083-C-CCCTGGCG is Pathogenic according to our data. Variant chr20-63407083-C-CCCTGGCG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 405212.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.2179_2180insCGCCAGG | p.Gly727AlafsTer140 | frameshift_variant | 17/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.2179_2180insCGCCAGG | p.Gly727AlafsTer140 | frameshift_variant | 17/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2017 | In summary, this is a novel frameshift variant that occurs upstream of a previously described pathogenic frameshift variant. This evidence indicates that the variant is also pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A different frameshift downstream of this variant (p.Cys744Leufs*91) has been determined to be pathogenic (PMID: 23692823). This suggests that disruption of this region of the KCNQ2 protein is causative of disease. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KCNQ2-related disease. This sequence change inserts 7 nucleotides in exon 17 of the KCNQ2 mRNA (c.2173_2179dupCGCCAGG), causing a frameshift at codon 727. This creates a premature translational stop signal in the last exon of the KCNQ2 mRNA (p.Gly727Alafs*140). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 145 amino acids of the KCNQ2 protein. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at