KCNMA1potassium large conductance calcium-activated channel, subfamily M, alpha member 1
Autism Reports / Total Reports
11 / 31Rare Variants / Common Variants
36 / 0Aliases
KCNMA1, SLO, BKTM, MaxiK, SAKCA, KCa1.1, MGC71881, SLO-ALPHA, DKFZp686K1437Associated Syndromes
-Chromosome Band
10q22.3Associated Disorders
-Relevance to Autism
Rare mutations in the KCNMA1 gene have been identified with autism (Laumonnier et al., 2006; Neale et al., 2012).
Molecular Function
The encoded protein is the pore forming alpha subunit of large conductance, voltage and calcium-sensitive potassium channels. These channels are fundamental to the control of smooth muscle tone and neuronal excitability.
External Links
SFARI Genomic Platforms
Reports related to KCNMA1 (31 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Highly Cited | Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure | Plger S , et al. (2000) | No | - |
| 2 | Recent Recommendation | Mechanism of increased open probability by a mutation of the BK channel | Dez-Sampedro A , et al. (2006) | No | - |
| 3 | Primary | Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation | Laumonnier F , et al. (2006) | Yes | MR |
| 4 | Recent Recommendation | Hydrophobic interface between two regulators of K+ conductance domains critical for calcium-dependent activation of large conductance Ca2+-activated K+ channels | Kim HJ , et al. (2006) | No | - |
| 5 | Recent Recommendation | BKCa-Cav channel complexes mediate rapid and localized Ca2+-activated K+ signaling | Berkefeld H , et al. (2006) | No | - |
| 6 | Recent Recommendation | Regulation of the gating of BKCa channel by lipid bilayer thickness | Yuan C , et al. (2007) | No | - |
| 7 | Recent Recommendation | Regulation of mouse Slo gene expression: multiple promoters, transcription start sites, and genomic action of estrogen | Kundu P , et al. (2007) | No | - |
| 8 | Recent Recommendation | Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons | Bell TJ , et al. (2008) | No | - |
| 9 | Recent Recommendation | The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels | Hou S , et al. (2008) | No | - |
| 10 | Recent Recommendation | Reciprocal regulation of the Ca2+ and H+ sensitivity in the SLO1 BK channel conferred by the RCK1 domain | Hou S , et al. (2008) | No | - |
| 11 | Support | Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy | Klassen T , et al. (2011) | No | - |
| 12 | Support | Patterns and rates of exonic de novo mutations in autism spectrum disorders | Neale BM , et al. (2012) | Yes | - |
| 13 | Recent Recommendation | Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder | Vardarajan BN , et al. (2013) | No | - |
| 14 | Support | Large-scale discovery of novel genetic causes of developmental disorders | Deciphering Developmental Disorders Study (2014) | No | - |
| 15 | Recent Recommendation | Low load for disruptive mutations in autism genes and their biased transmission | Iossifov I , et al. (2015) | Yes | - |
| 16 | Recent Recommendation | De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia | Takata A , et al. (2016) | No | - |
| 17 | Support | Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder | Lim ET , et al. (2017) | Yes | - |
| 18 | Support | Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants | Lecoquierre F , et al. (2019) | No | - |
| 19 | Support | De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes | Liang L , et al. (2019) | No | - |
| 20 | Support | Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort | Wu H , et al. (2019) | Yes | Macrocephaly |
| 21 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
| 22 | Support | A Gain-of-Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy | Zhang G et al. (2020) | Yes | Dystonia |
| 23 | Support | - | Zou D et al. (2021) | No | - |
| 24 | Support | - | Miller JP et al. (2021) | No | - |
| 25 | Support | - | Pode-Shakked B et al. (2021) | No | - |
| 26 | Support | - | Mahjani B et al. (2021) | Yes | - |
| 27 | Support | - | Perche O et al. (2022) | Yes | - |
| 28 | Support | - | Zhou X et al. (2022) | Yes | - |
| 29 | Support | - | et al. () | Yes | - |
| 30 | Support | - | et al. () | No | - |
| 31 | Highly Cited | A novel calcium-sensing domain in the BK channel | Schreiber M and Salkoff L (1997) | No | - |
Rare Variants (36)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.971C>T | p.Ser324Leu | missense_variant | Unknown | - | - | 37943464 | et al. () | |
| c.2481C>G | p.Ile827Met | stop_gained | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2322+1765G>T | - | splice_site_variant | Unknown | - | - | 34145886 | Zou D et al. (2021) | |
| c.2104+10495C>A | - | missense_variant | De novo | - | - | 28714951 | Lim ET , et al. (2017) | |
| c.3059A>G | p.Asp1020Gly | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1606A>C | p.Asn536His | missense_variant | De novo | - | - | 32633875 | Zhang G et al. (2020) | |
| c.1052C>A | p.Ser351Tyr | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| c.1066G>A | p.Gly356Arg | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| c.1123G>A | p.Gly375Arg | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| c.1987A>G | p.Ile663Val | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| c.2414C>T | p.Pro805Leu | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| c.2950G>A | p.Val984Ile | missense_variant | De novo | - | - | 31152168 | Liang L , et al. (2019) | |
| - | - | translocation | De novo | - | Possible multiplex | 16946189 | Laumonnier F , et al. (2006) | |
| - | p.Asn449fs | frameshift_variant | Familial | Paternal | - | 31152168 | Liang L , et al. (2019) | |
| c.3482C>G | p.Pro1161Arg | missense_variant | Unknown | - | - | 34615535 | Mahjani B et al. (2021) | |
| c.3364dup | p.Met1122AsnfsTer4 | frameshift_variant | De novo | - | Simplex | 37805537 | et al. () | |
| c.27_56del | p.Gly13_Ser22del | inframe_deletion | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.2923G>C | p.Asp975His | missense_variant | De novo | - | Simplex | 35982159 | Zhou X et al. (2022) | |
| c.G3248G>A | p.Arg1083Lys | missense_variant | De novo | - | Simplex | 31674007 | Wu H , et al. (2019) | |
| c.1123G>A | p.Gly375Arg | missense_variant | De novo | - | - | 31036916 | Lecoquierre F , et al. (2019) | |
| c.2984A>G | p.Asn995Ser | missense_variant | Unknown | - | - | 34580403 | Pode-Shakked B et al. (2021) | |
| c.2104+10495C>A | - | intron_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.1334A>G | p.Asn445Ser | missense_variant | De novo | - | Multiplex | 35982159 | Zhou X et al. (2022) | |
| c.762G>A | p.Thr254= | synonymous_variant | De novo | - | Simplex | 22495311 | Neale BM , et al. (2012) | |
| c.1114T>G | p.Phe372Val | missense_variant | De novo | - | Simplex | 22495311 | Neale BM , et al. (2012) | |
| c.1347C>T | p.Asn449%3D | synonymous_variant | De novo | - | Multiplex | 35982159 | Zhou X et al. (2022) | |
| c.2727G>A | p.Arg909%3D | synonymous_variant | De novo | - | Multiplex | 35982159 | Zhou X et al. (2022) | |
| c.1238G>A | p.Cys413Tyr | missense_variant | Familial | Maternal | - | 31152168 | Liang L , et al. (2019) | |
| c.2229T>C | p.Ser743= | synonymous_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| c.2967G>A | p.Val989= | synonymous_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| c.413C>T | p.Ala138Val | missense_variant | Unknown | - | Simplex | 16946189 | Laumonnier F , et al. (2006) | |
| c.762G>A | p.Thr254= | synonymous_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.1606A>C | p.Asn536His | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.2935G>C | p.Ala979Pro | missense_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| NM_001014797.3:g.78374737A>G | p.? | splice_site_variant | Unknown | - | Unknown | 21703448 | Klassen T , et al. (2011) | |
| c.1223+2705C>T | - | intron_variant | De novo | - | Unknown | 25533962 | Deciphering Developmental Disorders Study (2014) |
Common Variants
No common variants reported.
SFARI Gene score
2
Strong Candidate
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
Score Delta: Score remained at 2
criteria met
See SFARI Gene'scoring criteriaWe considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.
4/1/2022
3
2
Decreased from 3 to 2
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
7/1/2020
3
3
Decreased from 3 to 3
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
1/1/2020
3
3
Decreased from 3 to 3
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
10/1/2019
4
3
Decreased from 4 to 3
New Scoring Scheme
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
7/1/2019
4
4
Decreased from 4 to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurolo...2019]7/1/2017
4
4
Decreased from 4 to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
4/1/2016
4
4
Decreased from 4 to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
Reports Added
[Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation.2006] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A novel calcium-sensing domain in the BK channel.1997] [Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2) spark/STOC coupling and elevated blood pressure.2000] [Mechanism of increased open probability by a mutation of the BK channel.2006] [Hydrophobic interface between two regulators of K conductance domains critical for calcium-dependent activation of large conductance Ca2+activate...2006] [BKCa-Cav channel complexes mediate rapid and localized Ca2+activated K signaling.2006] [Regulation of the gating of BKCa channel by lipid bilayer thickness.2007] [Regulation of mouse Slo gene expression: multiple promoters, transcription start sites, and genomic action of estrogen.2007] [Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons.2008] [The RCK1 high-affinity Ca2 sensor confers carbon monoxide sensitivity to Slo1 BK channels.2008] [Reciprocal regulation of the Ca2 and H sensitivity in the SLO1 BK channel conferred by the RCK1 domain.2008] [Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.2013] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]1/1/2016
4
4
Decreased from 4 to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
Reports Added
[Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation.2006] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [A novel calcium-sensing domain in the BK channel.1997] [Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2) spark/STOC coupling and elevated blood pressure.2000] [Mechanism of increased open probability by a mutation of the BK channel.2006] [Hydrophobic interface between two regulators of K conductance domains critical for calcium-dependent activation of large conductance Ca2+activate...2006] [BKCa-Cav channel complexes mediate rapid and localized Ca2+activated K signaling.2006] [Regulation of the gating of BKCa channel by lipid bilayer thickness.2007] [Regulation of mouse Slo gene expression: multiple promoters, transcription start sites, and genomic action of estrogen.2007] [Cytoplasmic BK(Ca) channel intron-containing mRNAs contribute to the intrinsic excitability of hippocampal neurons.2008] [The RCK1 high-affinity Ca2 sensor confers carbon monoxide sensitivity to Slo1 BK channels.2008] [Reciprocal regulation of the Ca2 and H sensitivity in the SLO1 BK channel conferred by the RCK1 domain.2008] [Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.2013] [Low load for disruptive mutations in autism genes and their biased transmission.2015]1/1/2015
4
4
Decreased from 4 to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
7/1/2014
No data
4
Increased from No data to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
4/1/2014
No data
4
Increased from No data to 4
Description
Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).
Krishnan Probability Score
Score 0.61943424155592
Ranking 87/25841 scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning
approach on a human brain-specific gene network. The method was first presented in Nat
Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed
in column G of supplementary table 3 (see:
http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser,
with the ability to view networks of associated ASD risk genes, can be found at
asd.princeton.edu.
ExAC Score
Score 0.99921660285155
Ranking 1020/18225 scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has
been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by
Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at
exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of-
function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of-
function mutations in autism in such a gene would be more likely to confer risk. For a full list of
pLI scores see:
ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle
aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score
Score 0.856
Ranking 186/239 scored genes
[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists
239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This
probability metric combines the evidence from de novo likely-gene- disrupting and missense
mutations and assesses it against the background mutation rate in unaffected individuals from the
University of Washingtonâs Exome Variant Sequence database (evs.gs.washington.edu/EVS/).
The list of probability scores can be found here:
www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/-
/DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score
Score 0.92841503725185
Ranking 10909/18665 scored genes
[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013),
and is a statistic that integrates evidence from both de novo and transmitted mutations.
It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233
(2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper
(the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score
Score 4
Ranking 313/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available
ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size,
and variant frequency in the general population. The approach was first presented in Mol Autism
7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from
that paper.
Zhang D Score
Score 0.3946008660272
Ranking 1523/20870 scored genes
[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures),
or D score, was developed to combine evidence from de novo loss-of- function mutation with
evidence from cell-type- specific gene expression in the mouse brain (specifically translational
profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with
positive D scores are more likely to be associated with autism risk, with higher-confidence genes
having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204-
215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in
supplementary table 2 from that paper.
Interactome
- Protein Binding
- DNA Binding
- RNA Binding
- Protein Modification
- Direct Regulation
- ASD-Linked Genes
Interaction Table
| Interactor Symbol | Interactor Name | Interactor Organism | Interactor Type | Entrez ID | Uniprot ID |
|---|---|---|---|---|---|
| actin | <span title="The name recommended by the UniProt consortium for this chain/part." class="tooltipped RECOMMENDED"><a href="#PRO_0000000775" onclick="uniprot.entryViews.openSectionForInternalLink('PRO_0000000775');">Actin, cytoplasmic 1, N-terminally processed</a> | Mouse | Protein Binding | 11461 | P60710 |
| KCNMB1 | Calcium-activated potassium channel subunit beta-1 | Human | Direct Regulation | 3779 | Q16558 |
| Neph1 | Kin of IRRE-like protein 1 | Mouse | Protein Binding | 170643 | Q80W68 |
| PP2a-a | Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform | Mouse | Protein Binding | 19052 | P63330 |
| pp2a-c | Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform | Mouse | Protein Binding | 19052 | P63330 |
| tubulin | Tubulin alpha-1A chain | Mouse | Protein Binding | 22142 | P68369 |