rs1057516101
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_172107.4(KCNQ2):c.926C>T(p.Ala309Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ2
NM_172107.4 missense, splice_region
NM_172107.4 missense, splice_region
Scores
10
3
2
Splicing: ADA: 0.6486
2
Clinical Significance
Conservation
PhyloP100: 9.77
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 15 ACMG points.
PM1
?
In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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, 0.924
PP5
?
Variant 20-63439599-G-A is Pathogenic according to our data. Variant chr20-63439599-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 369772.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.926C>T | p.Ala309Val | missense_variant, splice_region_variant | 6/17 | ENST00000359125.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ2 | ENST00000359125.7 | c.926C>T | p.Ala309Val | missense_variant, splice_region_variant | 6/17 | 1 | NM_172107.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 7 Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Génétique des Maladies du Développement, Hospices Civils de Lyon | Aug 10, 2017 | - - |
not provided, no classification provided | literature only | GeneReviews | - | EE (epileptic encephalopathy) - |
Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2020 | This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with KCNQ2-related conditions (PMID: 23692823, 29314763, 30776697). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 369772). This sequence change replaces alanine with valine at codon 309 of the KCNQ2 protein (p.Ala309Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
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
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
Uncertain
D;D;D;D;D;.;D;D;D;D;D
Polyphen
D;.;.;.;.;.;D;.;D;D;.
Vest4
MutPred
Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);.;Loss of glycosylation at S314 (P = 0.3536);.;Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);Loss of glycosylation at S314 (P = 0.3536);
MVP
MPC
2.8
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at