20-63439623-C-T

Position:

chr20-63439623-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):c.902G>A(p.Gly301Asp) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G301S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.96

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]

KCNQ2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a transmembrane_region Helical; Name=Segment S6 (size 20) in uniprot entity KCNQ2_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_172107.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-63439624-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNQ2. . Gene score misZ: 4.0411 (greater than the threshold 3.09). Trascript score misZ: 3.6968 (greater than threshold 3.09). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. GenCC has associacion of the gene with seizures, benign familial neonatal, 1, neonatal-onset developmental and epileptic encephalopathy, benign familial neonatal-infantile seizures, benign neonatal seizures, malignant migrating partial seizures of infancy, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, developmental and epileptic encephalopathy, 7, benign familial infantile epilepsy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 20-63439623-C-T is Pathogenic according to our data. Variant chr20-63439623-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 431095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63439623-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.902G>A	p.Gly301Asp	missense_variant	6/17	ENST00000359125.7	NP_742105.1	O43526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 link	c.902G>A	p.Gly301Asp	missense_variant	6/17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

KCNQ2-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2023

The KCNQ2 c.902G>A variant is predicted to result in the amino acid substitution p.Gly301Asp. This variant has been reported with de novo occurrence in at least two individuals with epileptic encephalopathy or an unspecified neurodevelopmental disorder (Lelieveld et al. 2016. PubMed ID: 27479843; Popp et al. 2017. PubMed ID: 29158550). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare or absent in the general population. Different missense variants affecting the same amino acid (p.Gly301Ser and p.Gly301Val) have been reported (in some cases as de novo) in individuals with epilepsy and neurodevelopmental disorders (see for example, Abidi et al. 2015. PubMed ID: 26007637; Lindy et al. 2018. PubMed ID: 29655203). The c.902G>A (p.Gly301Asp) variant resides in the ion channel S6 motif adjacent to the selectivity filter, and this region is enriched for disease associated variants (HGMD; Lelieveld et al. 2017. PubMed ID: 28867141). This variant is interpreted as pathogenic. -

Seizures, benign familial neonatal, 1;C3150986:Developmental and epileptic encephalopathy, 7

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Center for Molecular Medicine, Children’s Hospital of Fudan University

Jul 07, 2020

- -

Seizure

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

Developmental and epileptic encephalopathy, 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Aug 01, 2017

De novo missense variant in a patient with developmental delay, hypotonia, seizures during first year of life. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

.;.;D;D;D;T;D;D;.;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;.;.;.;.;.;H;.;H;H;H

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.4

.;.;.;.;D;.;D;.;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;.;.;.;D;.;D;.;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;.;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;.

Vest4

0.98

MutPred

0.78

Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);.;Loss of catalytic residue at V302 (P = 0.1058);.;Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);Loss of catalytic residue at V302 (P = 0.1058);

MVP

1.0

MPC

3.3

ClinPred

1.0

GERP RS

4.0

Varity_R

0.98

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over