KCNT1

Chr 9AD

potassium sodium-activated channel subfamily T member 1

Also known as: DEE14, EIEE14, ENFL5, KCa4.1, KNa1.1, SLACK, Slo2.2, bA100C15.2

NCBI Gene: 57582 ENSG00000107147 UniProt: Q5JUK3 OMIM: 608167

This gene encodes a sodium-activated potassium channel subunit that regulates neuronal excitability and is involved in developmental signaling pathways. Mutations cause autosomal dominant epileptic disorders including developmental and epileptic encephalopathy 14 (malignant migrating partial seizures of infancy) and nocturnal frontal lobe epilepsy. Pathogenic variants predominantly cause disease through gain-of-function effects that alter channel conductance properties.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a sodium-activated potassium channel subunit which is thought to function in ion conductance and developmental signaling pathways. Mutations in this gene cause the early-onset epileptic disorders, malignant migrating partial seizures of infancy and autosomal dominant nocturnal frontal lobe epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.472 OMIM phenotypes

Clinical Summary— KCNT1

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Gene-Disease Validity (ClinGen)

childhood-onset epilepsy syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — 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

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.000

Z-score 4.92

OE 0.32 (0.23–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.86Z-score

OE missense 0.72 (0.67–0.77)

571 obs / 798.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.32 (0.23–0.47)

0≤0.351.4

Missense OE?0.72 (0.67–0.77)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 20 / 61.7Missense obs/exp: 571 / 798.3Syn Z: -3.71

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNT1-related epilepsyOTHERAD

definitiveKCNT1-related malignant migrating partial seizures of infancyGOFAD

This gene — mechanism propensity

0.6743th %ile

GOF

0.73top 25%

LOF

0.3065th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFTo date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Ohtahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016).1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References