Human Gene Module / Chromosome 5 / CAMK2A

CAMK2Acalcium/calmodulin dependent protein kinase II alpha

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 13
Rare Variants / Common Variants
22 / 1
Aliases
CAMK2A, CAMKA
Associated Syndromes
-
Chromosome Band
5q32
Associated Disorders
ASD
Relevance to Autism

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; additional functional characterizaton in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Molecular Function

The product of this gene belongs to the serine/threonine protein kinases family, and to the Ca(2+)/calmodulin-dependent protein kinases subfamily. The alpha chain encoded by this gene is required for hippocampal long-term potentiation (LTP) and spatial learning. In addition to its calcium-calmodulin (CaM)-dependent activity, this protein can undergo autophosphorylation, resulting in CaM-independent activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CAMK2A (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Recent Recommendation A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors Stephenson JR , et al. (2017) No -
3 Recent Recommendation De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability Kry S , et al. (2017) No Autistic features
4 Positive Association Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities Chiocchetti AG , et al. (2017) Yes Non-verbal communication (ADI-R Domains B1 + B4)
5 Support De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders Akita T , et al. (2018) No Autistic behavior, stereotypies
6 Support A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability Chia PH , et al. (2018) No -
7 Recent Recommendation The CaMKII/NMDA receptor complex controls hippocampal synaptic transmission by kinase-dependent and independent mechanisms Incontro S , et al. (2018) No -
8 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
9 Support - Yong XLH et al. (2021) No -
10 Support - Brea-Fernández AJ et al. (2022) No -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Sheth F et al. (2023) Yes DD, ID
13 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.817-1G>A - splice_site_variant De novo - - 29100089 Kry S , et al. (2017)
c.293T>C p.Phe98Ser missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.327G>C p.Glu109Asp missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.335C>T p.Ala112Val missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.635C>T p.Pro212Leu missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.704C>T p.Pro235Leu missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.845A>G p.His282Arg missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.856A>C p.Thr286Pro missense_variant De novo - - 29100089 Kry S , et al. (2017)
c.635C>T p.Pro212Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.666C>A p.Tyr222Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.704C>T p.Pro235Leu missense_variant De novo - - 29560374 Akita T , et al. (2018)
c.817-1G>A - splice_site_variant De novo - Simplex 29560374 Akita T , et al. (2018)
c.415G>A p.Glu139Lys missense_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.1205G>A p.Gly402Asp splice_site_variant De novo - - 29100089 Kry S , et al. (2017)
c.598+2dup - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.65del p.Gly22GlufsTer10 frameshift_variant Unknown - - 29100089 Kry S , et al. (2017)
c.635C>T p.Pro212Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.884C>A p.Ala295Asp missense_variant De novo - Simplex 37543562 Sheth F et al. (2023)
c.412-1G>T - splice_site_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.635C>A p.Pro212Gln missense_variant De novo - Simplex 29560374 Akita T , et al. (2018)
c.548A>T p.Glu183Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1429C>T p.His477Tyr missense_variant Familial Both parents Multiplex 29784083 Chia PH , et al. (2018)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1410T>C;c.1377G>A p.(=) synonymous_variant - - - 29147782 Chiocchetti AG , et al. (2017)
SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We 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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Reports Added
[Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
10/1/2017
4
icon
4S

Decreased from 4 to 4S

Description

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice. A de novo intronic variant adjacent to the splice donor site of the CAMK2A gene was identified in another ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; in silico analysis performed in Kury et al., 2017 predicted that this variant resulted in skipping of in-frame CAMK2A exon 8 and a partial loss of the CAMK2A kinase domain. Kury et al., 2017 reported an additional 12 individuals with intellectual disability and CAMK2A variants, several of which were experimentally shown to be either loss-of-function or gain-of-function variants; three of these individuals also presented with autistic features.

Reports Added
[De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.2017] [Common functional variants of the glutamatergic system in Autism spectrum disorder with high and low intellectual abilities.2017]
1/1/2017
icon
4

Increased from to 4

Description

A de novo missense variant in the CAMK2A gene (c.548A>T;p.Glu183Val) was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. Additional functional characterization in Stephenson et al., 2017 demonstrated the p.Glu183Val missense variant disrupted multiple CaMKII functions, induced synaptic deficits and caused ASD-related behavioral alterations in mice.

Krishnan Probability Score

Score 0.61200033730471

Ranking 183/25841 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.
Original Source
ExAC Score

Score 0.99800422080877

Ranking 1256/18225 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
Original Source
Sanders TADA Score

Score 0.73064886858655

Ranking 1379/18665 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).
Original Source
Zhang D Score

Score 0.40815767460412

Ranking 1367/20870 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.
Original Source
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