KCNMA1

protein-coding

potassium calcium-activated channel subfamily M alpha 1, the group of Potassium calcium-activated channels

Gene summary

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]

Previous symbols:

MANE transcript

NM_001161352.2

Inheritance

AD, AR

ClinVar variants

P:61U:578B:378

Top phenotype

Epilepsy, idiopathic generalized, susceptibility to, 16; Liang-Wang syndrome; Paroxysmal nonkinesigenic dyskinesia 3 with or without generalized epilepsy; Cerebellar atrophy, developmental delay, and seizures

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr10:76,869,601-77,638,369

External References & Databases

Ensembl (ENSG00000156113)

Transcript & Mutation Effects

hg38 • Region Span ~768.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

generalized epilepsy-paroxysmal dyskinesia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: Labcorp Genetics (formerly Invitae)

generalized epilepsy-paroxysmal dyskinesia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: G2P

generalized epilepsy-paroxysmal dyskinesia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: Ambry Genetics

cerebellar atrophy, developmental delay, and seizuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060551

Submitter: G2P

generalized epilepsy-paroxysmal dyskinesia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: Orphanet

cerebellar atrophy, developmental delay, and seizuresMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0060551

Submitter: Ambry Genetics

Liang-Wang syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032886

Submitter: Ambry Genetics

cerebellar atrophy, developmental delay, and seizuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060551

Submitter: Labcorp Genetics (formerly Invitae)

generalized epilepsy-paroxysmal dyskinesia syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012276

Submitter: ClinGen

The KCNMA1 gene is associated with an autosomal recessive clinical disorder characterized by a movement disorder, seizures, cerebellar atrophy, and developmental delay in the literature (OMIM 617643). Recent reviews evaluating the phenotype of previously reported patients indicate that homozygous or compound heterozygous variants in KCNMA1 are associated with disorder causing a spectrum of clinical phenotypes consistent with generalized epilepsy-paroxysmal dyskinesia syndrome (PMID 34224328, 31427379). Of note, this gene has also been implicated in autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome, which has been assessed separately. KCNMA1 was first reported in relation to an autosomal recessive generalized epilepsy-paroxysmal dyskinesia syndrome in 2016 (PMID 27567911). The mechanism for disease is homozygous or compound heterozygous loss-of-function variants. At least 4 unique variants, including nonsense, frameshift, and missense substitutions, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least three unrelated probands in three publications (PMIDs: 31152168, 27567911, 29545233). Variants in this gene segregated with disease in two siblings from a single family (PMID: 27567911). Parents who were heterozygous for truncating variants were reported to be unaffected (PMIDs: 31152168, 27567911, 29545233). Although the autosomal dominant and autosomal recessive KCNMA1 disorders share overlapping clinical features, the mechanism of disease may be different since haploinsufficiency did not result in clinical features of autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome in relatives who were heterozygous for truncating variants (PMID: 31152168). The autosomal recessive KCNMA1 gene-disease association is supported by an animal model (PMID: 35095492 29545233). In summary, there is moderate evidence to support this gene disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel Working Group on March 1, 2022 (SOP Version 8).

generalized epilepsy-paroxysmal dyskinesia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: PanelApp Australia

generalized epilepsy-paroxysmal dyskinesia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: ClinGen

The KCNMA1 gene is associated with autosomal dominant clinical disorders referred to as Liang-Wang syndrome (OMIM 618729) and paroxysmal nonkinesigenic dyskinesia (PNKD) type 3 with our without epilepsy (OMIM 609446) in the literature. Recent reviews evaluating the phenotype of previously reported patients indicate heterozygous variants in KCNMA1 are associated with a disorder that has a spectrum of clinical phenotypes (PMID 34224328, 31427379). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) or phenotypic variability. Therefore, all of the autosomal dominant disease entities have been lumped into one disease entity, autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome. Of note, this gene has also been implicated in autosomal recessive generalized epilepsy-paroxysmal dyskinesia syndrome, which has been assessed separately. KCNMA1 was first reported in relation to an autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome in 2005 (PMID 15937479). The gene encodes the pore-forming alpha subunit of the “Big K+” (BK) large conductance calcium and voltage-activated K+ channel. The mechanism for disease is heterozygous missense variants that may have either gain-of-function or loss-of-function effect on the BK potassium channel activity measured by patch clamp recording or expression in Xenopus laevis oocytes (PMID 34224328, 31152168, 15937479). At least 11 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least sixteen probands in eight publications (PMIDs: 15937479, 31152168, 26195193, 29330545, 29356177, 32633875, 34499417, 32132200). Variants in this gene segregated with disease in sixteen affected individuals with epilepsy, paroxysmal nonkinesigenic dyskinesia, or both (n = 5) over three generations in a large family (PMID: 15937479). Additionally, two recurrent de novo variants, p.(Gly375Arg) and p.(Asn1053Ser) (published as p.(Asn995Ser) using an alternative reference sequence) have been identified in multiple individuals with a similar phenotype (PMID: 31152168, 26195193, 29330545, 34499417). The maximum score for genetic evidence (12 pts.) has been reached. In summary, KCNMA1 is definitively associated with autosomal dominant generalized epilepsy-paroxysmal dyskinesia syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel Working Group on March 1, 2022 (SOP Version 8).

cerebellar atrophy, developmental delay, and seizuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0060551

Submitter: PanelApp Australia

generalized epilepsy-paroxysmal dyskinesia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012276

Submitter: Illumina

Clinical Genomic Database (CGD)

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15937479; 27567911; 29330545; 31152168

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNMA1 variants in ClinVar

19 Conditions Cataloged

Generalized epilepsy-paroxysmal dyskinesia syndromeTotal: 1108

not providedTotal: 494

not specifiedTotal: 148

KCNMA1-related disorderTotal: 97

Inborn genetic diseasesTotal: 87

Liang-Wang syndromeTotal: 47

Cerebellar atrophy, developmental delay, and seizuresTotal: 33

Epilepsy, idiopathic generalized, susceptibility to, 16Total: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001161352.2. 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			11 clinvar	353 clinvar	5 clinvar	369
missense	7 clinvar	23 clinvar	551 clinvar	19 clinvar	1 clinvar	601
nonsense	3 clinvar	2 clinvar	5 clinvar			10
start loss			2 clinvar			2
frameshift	9 clinvar	9 clinvar	4 clinvar			22
splice donor/acceptor (+/-2bp)		8 clinvar	5 clinvar			13
Total	19	42	578	372	6	1017

Highest pathogenic variant AF is 0.00021478397

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 171 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001161352.2	RefSeq	NP_001154824.1	28	MANE Select
ENST00000286628.14	Ensembl	ENSP00000286628.8	28	MANE Select
NM_001014797.3	RefSeq	NP_001014797.1	29	Standard
NM_001161353.2	RefSeq	NP_001154825.1	28	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kcnma1b	Danio rerio	Structure: swimming behavior Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

kcnma1b

Danio rerio

Structure: swimming behavior

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vascular smooth muscle contraction - Homo sapiens (human)
Renin secretion - Homo sapiens (human)
Salivary secretion - Homo sapiens (human)
Pancreatic secretion - Homo sapiens (human)
cGMP-PKG signaling pathway - Homo sapiens (human)

Biological Process

response to hypoxia
potassium ion transport
response to osmotic stress
cellular potassium ion homeostasis
response to carbon monoxide

Molecular Function

actin binding
voltage-gated potassium channel activity
protein binding
calcium-activated potassium channel activity
outward rectifier potassium channel activity

Cellular Component

plasma membrane
caveola
voltage-gated potassium channel complex
integral component of membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000404857
Coding exons: 28
Length: 768995
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.06	311	683	0.455	0.0000416	8042
Missense (PolyPhen)		63	270.96	0.2325		3202
Synonymous	-2.35	326	276	1.18	0.0000183	2335
Loss of Function	6.08	10	61.5	0.163	0.00000313	730

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+). It is also activated by the concentration of cytosolic Mg(2+). Its activation dampens the excitatory events that elevate the cytosolic Ca(2+) concentration and/or depolarize the cell membrane. It therefore contributes to repolarization of the membrane potential. Plays a key role in controlling excitability in a number of systems, such as regulation of the contraction of smooth muscle, the tuning of hair cells in the cochlea, regulation of transmitter release, and innate immunity. In smooth muscles, its activation by high level of Ca(2+), caused by ryanodine receptors in the sarcoplasmic reticulum, regulates the membrane potential. In cochlea cells, its number and kinetic properties partly determine the characteristic frequency of each hair cell and thereby helps to establish a tonotopic map. Kinetics of KCNMA1 channels are determined by alternative splicing, phosphorylation status and its combination with modulating beta subunits. Highly sensitive to both iberiotoxin (IbTx) and charybdotoxin (CTX).;
Disease: DISEASE: Paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy (PNKD3) [MIM:609446]: An autosomal dominant neurologic disorder characterized by absence seizures, generalized tonic-clonic seizures, paroxysmal nonkinesigenic dyskinesia and involuntary dystonic or choreiform movements. Onset is usually in childhood. Patients may have seizures only, dyskinesia only, or both. {ECO:0000269|PubMed:15937479, ECO:0000269|PubMed:26195193}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.140

Intolerance Scores

LoFtool: 0.0246
RVIS EVS: -1.68
RVIS percentile EVS: 2.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.348

Gene Damage Prediction

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