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rs118192208

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_172107.4(KCNQ2):​c.807G>T​(p.Trp269Cys) variant causes a missense 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W269L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 29)

Consequence

KCNQ2
NM_172107.4 missense

Scores

12
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.73
Variant links:
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 13 ACMG points.

PM1
?
    PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_172107.4
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
    PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chr20-63442416-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 205881.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, KCNQ2
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.942
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 20-63442415-C-A is Pathogenic according to our data. Variant chr20-63442415-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1700189.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ2NM_172107.4 linkuse as main transcriptc.807G>T p.Trp269Cys missense_variant 5/17 ENST00000359125.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ2ENST00000359125.7 linkuse as main transcriptc.807G>T p.Trp269Cys missense_variant 5/171 NM_172107.4 A1O43526-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
29
GnomAD4 exome
Cov.:
33
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
Cov.:
29

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Seizures, benign familial neonatal, 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
31
DANN
Uncertain
0.99
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.7
H;.;.;.;.;.;H;.;H;H;H;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.93
D
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;D;D;D;D;D;T
Polyphen
0.98
D;.;.;.;.;.;D;.;D;D;.;.
Vest4
0.97
MutPred
0.55
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;
MVP
0.99
MPC
3.5
ClinPred
1.0
D
GERP RS
3.4
Varity_R
0.96
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-62073768; API