KCNT1

protein-coding

potassium sodium-activated channel subfamily T member 1, the group of Potassium sodium-activated channel subfamily T

Gene summary

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]

MANE transcript

NM_020822.3

Inheritance

ClinVar variants

P:91U:917B:814

Top phenotype

Epilepsy, nocturnal frontal lobe, 5; Developmental and epileptic encephalopathy 14

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr9:135,702,185-135,795,508

External References & Databases

Ensembl (ENSG00000107147)

Transcript & Mutation Effects

hg38 • Region Span ~93.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

malignant migrating partial seizures of infancyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: G2P

childhood-onset epilepsy syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020072

Submitter: ClinGen

*KCNT1* was first reported in patients with childhood-onset epilepsy syndrome (MONDO:0020072) in 2012 (Barcia et al., PMID:23086397). Patients present in childhood with features including seizures, delayed myelination, and developmental delays. Five missense variants reported in eight probands across two publications are included in this curation (PMIDs: 23086397, 24029078). Of note, a number of recurrent variants have been observed, including p.Ala934Thr, p.Arg428Gln, p.Arg474His, p.Ile760Met, and p.Gly288Ser. More evidence may be available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity for early-onset epilepsy in *KCNT1* is thought to be gain-of-function (GOF) (PMIDs: 23086397, 26725113). This gene-disease relationship is also supported by expression and functional alteration studies (PMIDs: 12442315, 10196543, 23086397, 26725113). In summary, there is a definitive relationship between *KCNT1* and childhood-onset epilepsy syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was originally evaluated by the ClinGen Epilepsy GCEP on August 1, 2017. It was re-evaluated on August 16, 2022. As a result of this reevaluation, scoring was updated to reflect the current SOP version 9 recommendations for case-level data. New evidence was also included to retain the definitive classification. This includes additional case-level data (PMIDs:29196579, 32167590) as well as a mouse model (PMID: 33113364).

developmental and epileptic encephalopathy, 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013989

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 14MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013989

Submitter: Ambry Genetics

autosomal dominant nocturnal frontal lobe epilepsy 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014002

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 14STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013989

Submitter: Labcorp Genetics (formerly Invitae)

malignant migrating partial seizures of infancySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017385

Submitter: Orphanet

autosomal dominant nocturnal frontal lobe epilepsy 5STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014002

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 14DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013989

Submitter: G2P

autosomal dominant nocturnal frontal lobe epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0020300

Submitter: Orphanet

autosomal dominant nocturnal frontal lobe epilepsy 5MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014002

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Epilepsy, nocturnal frontal lobe, 5; Developmental and epileptic encephalopathy 14AD

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: 18479385; 23086396; 23086397; 23599387; 28331464

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNT1 variants in ClinVar

28 Conditions Cataloged

Developmental and epileptic encephalopathy, 14Total: 2151

Autosomal dominant nocturnal frontal lobe epilepsy 5Total: 2116

not providedTotal: 707

not specifiedTotal: 406

Inborn genetic diseasesTotal: 335

KCNT1-related disorderTotal: 96

SeizureTotal: 6

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020822.3. 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			19 clinvar	619 clinvar	12 clinvar	650
missense	26 clinvar	59 clinvar	816 clinvar	172 clinvar	6 clinvar	1079
nonsense		1 clinvar	18 clinvar			19
start loss						0
frameshift		3 clinvar	39 clinvar	4 clinvar		46
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	25 clinvar	1 clinvar		28
Total	27	64	917	796	18	1822

Highest pathogenic variant AF is 0.000013018137

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020822.3	RefSeq	NP_065873.2	31	MANE Select
ENST00000371757.7	Ensembl	ENSP00000360822.2	31	MANE Select
NM_001272003.2	RefSeq	NP_001258932.1	31	Standard
ENST00000263604.5	Ensembl	ENSP00000263604.4	31	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of membrane potential
potassium ion transmembrane transport

Molecular Function

intracellular sodium activated potassium channel activity
outward rectifier potassium channel activity

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000371757
Coding exons: 31
Length: 90962
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 125746
p: 0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.86	571	798	0.715	0.0000550	7996
Missense (PolyPhen)		100	196.28	0.50948		1836
Synonymous	-3.71	447	358	1.25	0.0000274	2417
Loss of Function	4.92	20	61.7	0.324	0.00000282	706

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.0011	0.0011	notable
East Asian	0.00022	0.00022	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00013	0.00013	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Outwardly rectifying potassium channel subunit that may coassemble with other Slo-type channel subunits. Activated by high intracellular sodium or chloride levels. Activated upon stimulation of G-protein coupled receptors, such as CHRM1 and GRIA1. May be regulated by calcium in the absence of sodium ions (in vitro) (By similarity). {ECO:0000250}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 14 (EIEE14) [MIM:614959]: A rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. This severe neurologic disorder is characterized by onset in the first 6 months of life of refractory focal seizures and arrest of psychomotor development. Ictal EEG shows discharges that arise randomly from various areas of both hemispheres and migrate from one brain region to another. {ECO:0000269|PubMed:23086397, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:24029078, ECO:0000269|PubMed:24463883, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epilepsy, nocturnal frontal lobe, 5 (ENFL5) [MIM:615005]: An autosomal dominant focal epilepsy syndrome characterized by childhood onset of clusters of motor seizures during sleep. Some patients may develop behavioral or psychiatric manifestations and/or intellectual disability. The phenotype is more severe than observed in other genetic forms of nocturnal frontal lobe epilepsy. {ECO:0000269|PubMed:23086396}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.577
RVIS EVS: -2.07
RVIS percentile EVS: 1.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.273

Gene Damage Prediction

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