rs1057516085

Variant names:

Variant summary

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

The NM_172107.4(KCNQ2):c.602G>A(p.Arg201His) 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. 13/21 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. R201C) 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:7O:2

Conservation

PhyloP100: 7.74

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; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNQ2_HUMAN there are 15 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 chr20-63444748-G-A is described in Lovd as [Pathogenic].

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 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, 0.987

PP5

Variant 20-63444747-C-T is Pathogenic according to our data. Variant chr20-63444747-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 369753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-63444747-C-T is described in Lovd as [Pathogenic]. Variant chr20-63444747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ2	NM_172107.4 link	c.602G>A	p.Arg201His	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.602G>A	p.Arg201His	missense_variant	Exon 4 of 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:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Mar 27, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate R201H stabilized the activated state of the channel producing a gain-of-function effect (PMID: 25740509); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27535030, 23708187, 27030113, 25880994, 28139826, 28867141, 29190809, 31440721, 35982159, 33057194, 25740509, 24107868, 35104249) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 7

Pathogenic:1Other:1

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS2_VSTR,PS4,PM1,PM5,PS3_SUP,PM2,PP3 -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

EE (epileptic encephalopathy) -

Severe intellectual deficiency

Pathogenic:1

Laboratory of Molecular Genetics, CHU Rennes

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Early infantile epileptic encephalopathy with suppression bursts

Pathogenic:1

Aug 01, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. The p.Arg201 amino acid residue in KCNQ2 has been determined to be clinically significant (PMID: 28139826, 27535030, 28867141). This suggests that variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change results in a protein that has a significant increase in current density and loss of voltage-dependent gating (PMID: 25740509) This variant has been reported to be de novo in several individuals affected with early infantile epileptic encephalopathy (PMID: 23708187, 25880994, 29190809, 28139826). ClinVar contains an entry for this variant (Variation ID: 369753). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 201 of the KCNQ2 protein (p.Arg201His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. -

Complex neurodevelopmental disorder

Other:1

Channelopathy-Associated Epilepsy Research Center

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

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

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.69

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

0.98

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.8

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

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98

MutPred

0.90

Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);.;Loss of MoRF binding (P = 0.0112);.;Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);Loss of MoRF binding (P = 0.0112);.;

MVP

0.99

MPC

3.1

ClinPred

1.0

GERP RS

3.9

Varity_R

0.89

gMVP

0.99

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