rs118192203

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_172107.4(KCNQ2):c.637C>T(p.Arg213Trp) 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. 13/22 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. R213L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KCNQ2
NM_172107.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 6.65

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 7
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
neonatal encephalopathy with non-epileptic myoclonus
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neonatal-onset developmental and epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
seizures, benign familial neonatal, 1
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
seizures, benign familial neonatal, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
benign familial infantile epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign familial neonatal-infantile seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
benign neonatal seizures
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant migrating partial seizures of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KCNQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr20-63444711-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1685899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the KCNQ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 319 curated pathogenic missense variants (we use a threshold of 10). The gene has 78 curated benign missense variants. Gene score misZ: 4.0411 (above the threshold of 3.09). Trascript score misZ: 3.6968 (above the threshold of 3.09). GenCC associations: The gene is linked to benign familial infantile epilepsy, malignant migrating partial seizures of infancy, developmental and epileptic encephalopathy, 7, benign familial neonatal-infantile seizures, benign neonatal seizures, neonatal-onset developmental and epileptic encephalopathy, complex neurodevelopmental disorder, seizures, benign familial neonatal, 2, seizures, benign familial neonatal, 1, neonatal encephalopathy with non-epileptic myoclonus.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 20-63444712-G-A is Pathogenic according to our data. Variant chr20-63444712-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 21795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.637C>T	p.Arg213Trp	missense_variant	Exon 4 of 17	ENST00000359125.7	NP_742105.1	O43526-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ2	ENST00000359125.7 link	c.637C>T	p.Arg213Trp	missense_variant	Exon 4 of 17	1	NM_172107.4	ENSP00000352035.2		O43526-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1444802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

716744

African (AFR)

AF:

0.00

AC:

AN:

33318

American (AMR)

AF:

0.00

AC:

AN:

42156

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25768

East Asian (EAS)

AF:

0.00

AC:

AN:

39058

South Asian (SAS)

AF:

0.00

AC:

AN:

83542

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51054

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104380

Other (OTH)

AF:

0.00

AC:

AN:

59780

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000619

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Mar 25, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that R213W decreases the stability of the ion channel and decreases voltage sensitivity (Miceli et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20437616, 24375629, 24318194, 22455920, 18353052, 29056246, 28038823, 27535030, 26993267, 25959266, 28717674, 27779742, 17765802, 22275249, 32139178, 31512412, 32917465, 32712949, 33726816, 31440721, 33659638, 31440733, 30440138, 23440208) -

Nov 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 18, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 7

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

BFNE (benign familial neonatal epilepsy), EE (epileptic encephalopathy) -

Oct 19, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Feb 02, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Nov 06, 2019

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R213W pathogenic mutation (also known as c.637C>T), located in coding exon 4 of the KCNQ2 gene, results from a C to T substitution at nucleotide position 637. The arginine at codon 213 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was detected in two siblings with BFNC (benign familial neonatal convulsions). Neither parent carried the mutation, and after parental relationships were confirmed, authors suspected germline mosaicism (Sadewa AH et al. Pediatr Int, 2008 Apr;50:167-71). In another study, this mutation was detected in an individual with EOEE (early onset epileptic encephalopathy) and was found to be mosaic in a parent (Milh M et al. Am. J. Med. Genet. A, 2015 Oct;167A:2314-8). In addition, this mutation has been detected in individuals with: non-specific epileptic encephalopathy, neonatal seizure disorder, congenital variant of Rett syndrome, and EIMFS (Epilepsy of Infancy with Migrating Focal Seizures) (Butler KM et al. Pediatr. Neurol., 2017 Dec;77:61-66; Zhang Q et al. Clin. Genet., 2017 May;91:717-724; Wang J et al. Mol Genet Genomic Med, 2019 Sep;:e968; Ware TL et al. Epilepsia Open, 2019 Sep;4:504-510). One functional study showed that this mutation destabilized the potassium ion channel and decreased voltage sensitivity (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91). In addition, a different alteration located at the same position, p.R213Q, has been detected in multiple individuals with epilepsy (Weckhuysen S et al. Ann. Neurol., 2012 Jan;71:15-25; Trump N et al. J. Med. Genet., 2016 May;53:310-7) and has been shown to result in a decrease in channel voltage sensitivity (Miceli F et al. Proc. Natl. Acad. Sci. U.S.A., 2013 Mar;110:4386-91; Orhan G et al. Ann. Neurol., 2014 Mar;75:382-94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Developmental and epileptic encephalopathy

Pathogenic:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 213 of the KCNQ2 protein (p.Arg213Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with benign familial neonatal seizures or early-onset epilepsy (PMID: 18353052, 27779742, 29056246). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21795). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNQ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 23440208). This variant disrupts the p.Arg213 amino acid residue in KCNQ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22275249, 25982755). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Seizures, benign familial neonatal, 1

Pathogenic:1

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

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

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

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

PhyloP100

6.7

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.2

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.94

Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);.;Loss of solvent accessibility (P = 0.086);.;Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);Loss of solvent accessibility (P = 0.086);.;

MVP

0.98

MPC

2.8

ClinPred

1.0

GERP RS

4.0

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.87

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over