Human Gene Module / Chromosome 10 / KCNMA1

KCNMA1potassium large conductance calcium-activated channel, subfamily M, alpha member 1

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 22
Rare Variants / Common Variants
23 / 0
Aliases
KCNMA1, SLO,  BKTM,  MaxiK,  SAKCA,  KCa1.1,  MGC71881,  SLO-ALPHA,  DKFZp686K1437
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
10q22.3
Associated 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.

Reports related to KCNMA1 (22 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+activate... 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 Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v... 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 neurolo... 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 Highly Cited A novel calcium-sensing domain in the BK channel. Schreiber M and Salkoff L (1997) No -
Rare Variants   (23)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2104+10495C>A - missense_variant De novo NA - 28714951 Lim ET , et al. (2017)
- p.Asn449fs frameshift_variant Familial Paternal - 31152168 Liang L , et al. (2019)
c.1052C>A p.Ser351Tyr missense_variant De novo NA - 31152168 Liang L , et al. (2019)
c.1066G>A p.Gly356Arg missense_variant De novo NA - 31152168 Liang L , et al. (2019)
c.1123G>A p.Gly375Arg missense_variant De novo NA - 31152168 Liang L , et al. (2019)
c.1987A>G p.Ile663Val missense_variant De novo NA - 31152168 Liang L , et al. (2019)
c.2414C>T p.Pro805Leu missense_variant De novo NA - 31152168 Liang L , et al. (2019)
c.2950G>A p.Val984Ile missense_variant De novo NA - 31152168 Liang L , et al. (2019)
- - translocation De novo NA Possible multiplex 16946189 Laumonnier F , et al. (2006)
c.G3248G>A p.Arg1083Lys missense_variant De novo NA Simplex 31674007 Wu H , et al. (2019)
c.1123G>A p.Gly375Arg missense_variant De novo NA - 31036916 Lecoquierre F , et al. (2019)
c.2104+10495C>A - intron_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1238G>A p.Cys413Tyr missense_variant Familial Maternal - 31152168 Liang L , et al. (2019)
c.762G>A p.Thr254= synonymous_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
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.1114T>G p.Phe372Val missense_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.413C>T p.Ala138Val missense_variant Unknown - Unknown 16946189 Laumonnier F , et al. (2006)
c.762G>A p.Thr254= synonymous_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1606A>C p.Asn536His missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.2935G>C p.Ala979Pro missense_variant De novo NA 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 NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

1/1/2020
4
icon
4

Score remained at 4

Description

Gene has one association study which is not genome-wide significant (Laumonnier et al., 2006).

10/1/2019
4
icon
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).

7/1/2017
4
icon
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
icon
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
icon
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
icon
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
icon
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
icon
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 Washington’s 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.
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
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