KCNQ2

Chr 20AD

potassium voltage-gated channel subfamily Q member 2

Also known as: BFNC, DEE7, EBN, EBN1, ENB1, HNSPC, KCNA11, KV7.2

NCBI Gene: 3785 ENSG00000075043 UniProt: O43526 OMIM: 602235

Encodes a voltage-gated potassium channel subunit that forms M channels with KCNQ3 to regulate neuronal excitability by controlling potassium efflux. Mutations cause autosomal dominant benign familial neonatal seizures, developmental and epileptic encephalopathy, and myokymia predominantly through loss-of-function mechanisms that reduce channel activity and increase neuronal excitability. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency being pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

MultiplemechanismADLOEUF 0.163 OMIM phenotypes

VCEP Guidelines: KCNQ Brain DisordersIn Progress

ClinGen Panel

Clinical Summary— KCNQ2

🧬

Gene-Disease Validity (ClinGen)

neonatal-onset developmental and epileptic encephalopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.16LOEUF

pLI 1.000

Z-score 5.55

OE 0.05 (0.02–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

4.04Z-score

OE missense 0.52 (0.47–0.57)

286 obs / 553.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.16)

0≤0.351.4

Missense OE0.52 (0.47–0.57)

0≤0.61.4

Synonymous OE1.09

0≤1.21.6

LoF obs/exp: 2 / 39.8Missense obs/exp: 286 / 553.6Syn Z: -1.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNQ2-related epileptic encephalopathyGOFAD

definitiveKCNQ2-related benign neonatal epilepsyLOFAD

0.6550th %ile

GOF

0.72top 25%

LOF

0.68top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.16

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy.PMID:24318194

GOFNeonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.PMID:28139826

LOFThese possibilities include haploinsufficiency of two epilepsy genes CHRNA4 and KCNQ2 located at 20qter, silencing of these genes by a telomere position effect, or microdeletions or rearrangements of genetic material during the ring formation.PMID:16835934

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.