KCNQ2

protein-coding

potassium voltage-gated channel subfamily Q member 2, the group of Potassium voltage-gated channels

Gene summary

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]

Previous symbols:

EBN
EBN1

MANE transcript

NM_172107.4

Inheritance

ClinVar variants

P:805U:670B:457

Top phenotype

Epileptic encephalopathy, early infantile, 7

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr20:63,400,208-63,472,677

External References & Databases

Ensembl (ENSG00000075043)

Transcript & Mutation Effects

hg38 • Region Span ~72.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

benign neonatal seizuresSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016027

Submitter: Orphanet

neonatal-onset developmental and epileptic encephalopathyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100455

Submitter: ClinGen

*KCNQ2* was first reported in relation to autosomal dominant neonatal-onset developmental and epileptic encephalopathy in 2012 (Weckhuysen et al., PMID: 22275249). Assertions have been made for a relationship between *KCNQ2* and several neurodevelopmental presentations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism and phenotypic variability between these assertions. Therefore, the curation has been split into multiple autosomal dominant disease entities: neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455; thought to be dominant negative), self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function), and neonatal encephalopathy with non-epileptic myoclonus (MONDO:0100456; thought to be gain of function). The split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455). Twenty-two missense variants that have been reported in 29 probands in three publications are included in this curation (PMIDs: 22275249, 24107868, 23621294). Probands display multiple features, including seizure onset as early as the first day of life and neurodevelopmental delays that range from moderate to severe. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is thought to be dominant negative (PMID: 24318194). This gene-disease relationship is also supported by animal models and functional alteration studies (PMIDs: 23440208, 24318194, 34911751). In summary, there is a definitive relationship between *KCNQ2* and autosomal dominant neonatal-onset developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on June 21, 2022 (SOP Version 9).

developmental and epileptic encephalopathy, 7SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013387

Submitter: Orphanet

benign familial infantile epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017615

Submitter: Orphanet

benign familial neonatal-infantile seizuresSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011140

Submitter: Orphanet

developmental and epileptic encephalopathy, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013387

Submitter: Labcorp Genetics (formerly Invitae)

neonatal encephalopathy with non-epileptic myoclonusDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100456

Submitter: ClinGen

*KCNQ2* was first reported in a proband with autosomal dominant neonatal encephalopathy with nonepileptic myoclonus in 2012 (Weckhuysen et al., PMID: 22275249). Assertions have been made for a relationship between *KCNQ2* and several neurodevelopmental presentations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism and phenotypic variability between these assertions. Therefore, the curation has been split into multiple autosomal dominant disease entities: neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455; thought to be dominant negative), self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function, attributed primarily to p.R230C/H/S, p.R198Q, and p.R144Q/W/G recurrent de novo variants), and neonatal encephalopathy with non-epileptic myoclonus (MONDO:0100456; thought to be gain of function, attributed to p.R201C, p.R201H, and p.V175L recurrent de novo variants). The split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant neonatal encephalopathy with nonepileptic myoclonus (MONDO:0100456). Three recurrent de novo missense variants, p.R201C, p.R201H, and p.V175L, reported in 12 probands in three publications, are included in this curation (PMIDs: 28139826, 23692823, 25092550). Patients often present with exaggerated startle responses and/or myoclonus within the first days or weeks or life, along with encephalopathy and hypotonia from birth (PMID: 28139826). Patients also commonly have respiratory insufficiency, central hypoventilation, a persistent suppression burst pattern of EEG background, and recurrent bouts of myoclonus that are not accompanied by epileptic discharges on electroencephalography (PMID: 28139826). Evolution to pharmacoresistant seizures is common, as is continued profound global developmental delay. The mechanism of pathogenicity is thought to be gain of function (PMIDs: 25740509, 27030113). In summary, there is a definitive relationship between *KCNQ2* and autosomal dominant neonatal encephalopathy with nonepileptic myoclonus. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on February 15, 2022 (SOP Version 8).

developmental and epileptic encephalopathy, 7DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013387

Submitter: G2P

neonatal-onset developmental and epileptic encephalopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100455

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 7STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013387

Submitter: PanelApp Australia

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: PanelApp Australia

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*KCNQ2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder (MONDO:0100038), which includes patients with overlapping neurodevelopmental features including autism, intellectual disability, and developmental delays, in 2013 (Epi4K Consortium et al., PMID: 23934111). Assertions have been made for a relationship between *KCNQ2* and several neurodevelopmental presentations. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we have found differences in molecular mechanism and phenotypic variability between these assertions. Therefore, the curation has been split into multiple autosomal dominant disease entities: neonatal-onset developmental and epileptic encephalopathy (MONDO:0100455; thought to be dominant negative), self-limited familial neonatal epilepsy (MONDO:0100023; thought to be loss of function), complex neurodevelopmental disorder (MONDO:0100038; thought to be gain of function, primarily attributed to p.R230C/H/S, p.R198Q, and p.R144Q/W/G recurrent de novo variants), and neonatal encephalopathy with non-epileptic myoclonus (MONDO:0100456; thought to be gain of function, attributed to p.R201C, p.R201H, and p.V175L recurrent de novo variants). The split curations have been curated separately by the Epilepsy GCEP and this entry will only cover autosomal dominant complex neurodevelopmental disorder (MONDO:0100038). Five missense variants that have been reported in 10 probands in four publications are included in this curation (PMIDs: 23934111, 26138355, 27861786, 33754465). Probands display multiple features, which can include developmental delays, autism, hypotonia, and intellectual disability. Some also have seizures, which onset at around 4-6 months of age. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is thought to be gain of function (PMID: 27861786, 25740509). In summary, there is a definitive relationship between *KCNQ2* and autosomal dominant complex neurodevelopmental disorder (MONDO:0100038). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on November 15, 2021 (SOP Version 8).

seizures, benign familial neonatal, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007366

Submitter: Labcorp Genetics (formerly Invitae)

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

seizures, benign familial neonatal, 1DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007365

Submitter: G2P

Clinical Genomic Database (CGD)

Epileptic encephalopathy, early infantile, 7AD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Individuals may manifest with seizures, and specific knowledge of the underlying cause can help direct selection of optimal therapies for management based on the genetic etiology

Refs: 7980108; 9430594; 9425895; 11572947; 12742592; 15249611; 16235065; 16966552; 17675531; 17872363; 19822871; 22169383; 22275249; 22884718; 22926866; 28331464

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNQ2 variants in ClinVar

43 Conditions Cataloged

Early-infantile DEETotal: 1619

not providedTotal: 775

Developmental and epileptic encephalopathy, 7Total: 321

Seizures, benign familial neonatal, 1Total: 250

not specifiedTotal: 230

Inborn genetic diseasesTotal: 216

KCNQ2-Related DisordersTotal: 133

SeizureTotal: 38

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_172107.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		3 clinvar	18 clinvar	406 clinvar	6 clinvar	433
missense	152 clinvar	287 clinvar	623 clinvar	43 clinvar	2 clinvar	1107
nonsense	57 clinvar	15 clinvar	5 clinvar			77
start loss	2 clinvar	3 clinvar				5
frameshift	174 clinvar	49 clinvar	14 clinvar			237
splice donor/acceptor (+/-2bp)	27 clinvar	36 clinvar	10 clinvar			73
Total	412	393	670	449	8	1932

Highest pathogenic variant AF is 0.000020584295

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 68 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_172107.4	RefSeq	NP_742105.1	17	MANE Select
ENST00000359125.7	Ensembl	ENSP00000352035.2	17	MANE Select
NM_001382235.1	RefSeq	NP_001369164.1	17	Standard
NM_001439003.1	RefSeq	NP_001425932.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cholinergic synapse - Homo sapiens (human)
Celecoxib Pathway, Pharmacodynamics
Splicing factor NOVA regulated synaptic proteins
Developmental Biology
ion channels and their functional role in vascular endothelium

Biological Process

chemical synaptic transmission
nervous system development
regulation of ion transmembrane transport
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity
protein binding
calmodulin binding
ankyrin binding

Cellular Component

plasma membrane
integral component of plasma membrane
voltage-gated potassium channel complex
integral component of membrane
node of Ranvier

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359125
Coding exons: 17
Length: 66452
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125744
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.04	286	554	0.517	0.0000396	5568
Missense (PolyPhen)		81	238.29	0.33993		2238
Synonymous	-1.18	285	261	1.09	0.0000213	1793
Loss of Function	5.55	2	39.8	0.0503	0.00000197	445

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000064	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Associates with KCNQ3 to form a potassium channel with essentially identical properties to the channel underlying the native M-current, a slowly activating and deactivating potassium conductance which plays a critical role in determining the subthreshold electrical excitability of neurons as well as the responsiveness to synaptic inputs. Therefore, it is important in the regulation of neuronal excitability. KCNQ2/KCNQ3 current is blocked by linopirdine and XE991, and activated by the anticonvulsant retigabine (PubMed:9836639, PubMed:11572947, PubMed:14534157, PubMed:12742592, PubMed:17872363). As the native M-channel, the potassium channel composed of KCNQ2 and KCNQ3 is also suppressed by activation of the muscarinic acetylcholine receptor CHRM1 (PubMed:10684873). {ECO:0000269|PubMed:10684873, ECO:0000269|PubMed:11572947, ECO:0000269|PubMed:12742592, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:17872363, ECO:0000269|PubMed:25740509, ECO:0000269|PubMed:9836639}.;
Disease: DISEASE: Seizures, benign familial neonatal 1 (BFNS1) [MIM:121200]: A disorder characterized by clusters of seizures occurring in the first days of life. Most patients have spontaneous remission by 12 months of age and show normal psychomotor development. Some rare cases manifest an atypical severe phenotype associated with epileptic encephalopathy and psychomotor retardation. The disorder is distinguished from benign familial infantile seizures by an earlier age at onset. In some patients, neonatal convulsions are followed later in life by myokymia, a benign condition characterized by spontaneous involuntary contractions of skeletal muscles fiber groups that can be observed as vermiform movement of the overlying skin. Electromyography typically shows continuous motor unit activity with spontaneous oligo- and multiplet-discharges of high intraburst frequency (myokymic discharges). Some patients may have isolated myokymia. {ECO:0000269|PubMed:11175290, ECO:0000269|PubMed:11572947, ECO:0000269|PubMed:14534157, ECO:0000269|PubMed:15249611, ECO:0000269|PubMed:23360469, ECO:0000269|PubMed:25982755, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:9425895}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 7 (EIEE7) [MIM:613720]: An autosomal dominant seizure disorder characterized by infantile onset of refractory seizures with resultant delayed neurologic development and persistent neurologic abnormalities. {ECO:0000269|PubMed:12742592, ECO:0000269|PubMed:15249611, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:25740509, ECO:0000269|PubMed:25818041, ECO:0000269|PubMed:26138355, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.00282
RVIS EVS: -0.67
RVIS percentile EVS: 15.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.832

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium