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

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
GOFmechanismADLOEUF 0.472 OMIM phenotypes
Clinical SummaryKCNT1
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Gene-Disease Validity (ClinGen)
childhood-onset epilepsy syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
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ClinVar Variants
15 unique Pathogenic / Likely Pathogenic· 134 VUS of 300 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
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GeneReview available — KCNT1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.47LOEUF
pLI 0.000
Z-score 4.92
OE 0.32 (0.230.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
2.86Z-score
OE missense 0.72 (0.670.77)
571 obs / 798.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.32 (0.230.47)
00.351.4
Missense OE0.72 (0.670.77)
00.61.4
Synonymous OE1.25
01.21.6
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
DN
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 · 80% of P/LP are missense
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).PMID:28366665

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

ClinVar Variant Classifications

300 submitted variants in ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic7
VUS134
Likely Benign128
Benign2
Conflicting14
8
Pathogenic
7
Likely Pathogenic
134
VUS
128
Likely Benign
2
Benign
14
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
2
0
8
Likely Pathogenic
0
7
0
0
7
VUS
14
114
4
2
134
Likely Benign
2
8
67
51
128
Benign
0
0
2
0
2
Conflicting
14
Total171347553293

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

KCNT1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold
Clinical Literature
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