KCNMA1

Chr 10ADAR

potassium calcium-activated channel subfamily M alpha 1

Also known as: BKTM, CADEDS, IEG16, KCa1.1, LIWAS, MaxiK, PNKD3, SAKCA

NCBI Gene: 3778 ENSG00000156113 UniProt: Q12791 OMIM: 600150

This gene encodes the alpha subunit of calcium-activated BK channels, which regulate smooth muscle contraction, neurotransmitter release, and neuronal excitability. Mutations cause a spectrum of autosomal dominant and autosomal recessive neurological disorders including generalized epilepsy, paroxysmal nonkinesigenic dyskinesia, cerebellar atrophy with developmental delay, and Liang-Wang syndrome. Disease mechanisms vary by variant type, with the gene showing high constraint against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

GeneReviews OMIM ResearchGenerating clinical summary…

GOF/LOFmechanismAD/ARLOEUF 0.284 OMIM phenotypes

Clinical Summary— KCNMA1

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Gene-Disease Validity (ClinGen)

generalized epilepsy-paroxysmal dyskinesia syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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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.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 704 VUS of 1547 total submissions

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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 →

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GeneReview available — KCNMA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.997

Z-score 6.08

OE 0.16 (0.10–0.28)

Highly constrained

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

Missense Constraint?

5.06Z-score

OE missense 0.46 (0.41–0.50)

311 obs / 683.4 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.16 (0.10–0.28)

0≤0.351.4

Missense OE?0.46 (0.41–0.50)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 10 / 61.5Missense obs/exp: 311 / 683.4Syn Z: -2.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKCNMA1-related generalized epilepsy and paroxysmal dyskinesiaGOFAD

strongKCNMA1-related developmental delay, seizures and cerebellar atrophyLOFAR

Mechanism Note (variant-dependent)

GOFLOF— mechanism depends on specific variant

BK channel (KCa1.1). D434G is well-characterized GOF causing GEPD. Other monoallelic variants cause LOF. Biallelic LOF variants cause cerebellar ataxia. Mechanism is variant-specific.1

This gene — mechanism propensity

0.4785th %ile

GOF

0.6052th %ile

LOF

0.67top 25%

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

LOFprediction above median · 1 literature citation · 59% of P/LP variants are LoF · LOEUF 0.28

GOF1 literature citation

DN1 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

DNIt is however also possible that some KCNMA1 missense LoF variants confer a higher degree of penetrance by a dominant negative mechanism by impacting multiple subunits and binding proteins of the BK channel Î±-subunit (2,20).2

GOFLoF variants of KCNMA1 cause a new syndrome distinctly different from gain-of-function variants in the same gene.2

LOFDe novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes2

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

References

ClinVar Variant Classifications

1547 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic31

VUS704

Likely Benign604

Benign81

Conflicting84

Pathogenic

Likely Pathogenic

704

VUS

604

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	12	7	1	0	20
Likely Pathogenic	18	11	2	0	31
VUS	15	593	84	12	704
Likely Benign	1	19	266	318	604
Benign	0	2	73	6	81
Conflicting	—				84
Total	46	632	426	336	1,524

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

View in ClinVar →

11 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap KCNMA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →