rs796052658
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_172107.4(KCNQ2):c.2245G>T(p.Glu749Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E749E) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KCNQ2
NM_172107.4 stop_gained
NM_172107.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.68
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 14 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 13 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 20-63407018-C-A is Pathogenic according to our data. Variant chr20-63407018-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 205931.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.2245G>T | p.Glu749Ter | stop_gained | 17/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.2245G>T | p.Glu749Ter | stop_gained | 17/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1373628Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 676064
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1373628
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36
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0
AN XY:
676064
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
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 | Oct 23, 2023 | This sequence change creates a premature translational stop signal (p.Glu749*) in the KCNQ2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 124 amino acid(s) of the KCNQ2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with in a cohort of individuals tested for epilepsy and/or neurodevelopmental disorders (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 205931). This variant disrupts a region of the KCNQ2 protein in which other variant(s) (p.Cys774Leufs*91) have been determined to be pathogenic (PMID: 23692823). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2013 | The Glu749Stop nonsense mutation in the KCNQ2 gene is predicted to cause loss of normal protein function through protein truncation, as the last 124 amino acids of the protein are lost. Although this mutation has not been reported previously to our knowledge, its presence is consistent with a diagnosis of a KCNQ2-related disorder. The variant is found in EPILEPSY panel(s). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
Vest4
GERP RS
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