Human Gene Module / Chromosome 20 / CSNK2A1

CSNK2A1casein kinase 2 alpha 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
4 / 19
Rare Variants / Common Variants
47 / 0
EAGLE Score
6.2
Moderate Learn More
Aliases
CSNK2A1, CK2A1,  CKII,  Cka1,  Cka2,  OCNDS
Associated Syndromes
Okur-Chung neurodevelopmental syndrome, DD, ID, Okur-Chung neurodevelopmental syndrome, ID, Okur-Chung neurodevelopmental syndrome
Chromosome Band
20p13
Associated Disorders
ADHD, ASD, EPS, ID
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Two rare de novo missense variants in the CSNK2A1 gene have been identified in ASD probands from simplex families from the Simons Simplex Collection (Iossifov et al., 2014) and the ASD: Genomes to Outcome Study cohort (Yuen et al., 2017). Heterozygous variants in the CSNK2A1 gene are also responsible for Okur-Chung neurodevelopmental syndrome (OMIM 617062), an autosomal dominant disorder characterized by delayed psychomotor development, intellectual disability with poor speech, behavioral abnormalities, cortical malformations in some patients, and variable dysmorphic facial features; autistic features and/or stereotypy has been reported in a subset of affected individuals (Okur et al., 2016; Trinh et al., 2017; Chiu et al., 2018; Owen et al., 2018, Martinez-Monseny et al., 2020).

Molecular Function

Casein kinase II is a serine/threonine protein kinase that phosphorylates acidic proteins such as casein. It is involved in various cellular processes, including cell cycle control, apoptosis, and circadian rhythm. The kinase exists as a tetramer and is composed of an alpha, an alpha-prime, and two beta subunits. The alpha subunits contain the catalytic activity while the beta subunits undergo autophosphorylation. The protein encoded by this gene represents the alpha subunit.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CSNK2A1 (19 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 Support De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features Okur V et al. (2016) No ADHD, epilepsy/seizures, stereotypy
3 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support A novel de novo mutation in CSNK2A1: reinforcing the link to neurodevelopmental abnormalities and dysmorphic features Trinh J et al. (2017) No Autistic features
5 Support Okur-Chung neurodevelopmental syndrome: Eight additional cases with implications on phenotype and genotype expansion Chiu ATG et al. (2018) No ASD or autistic features, stereotypy, epilepsy/sei
6 Support Extending the phenotype associated with the CSNK2A1-related Okur-Chung syndrome-A clinical study of 11 individuals Owen CI et al. (2018) No Autistic features, stereotypy
7 Support Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome Akahira-Azuma M et al. (2018) No -
8 Support Identification of de novo CSNK2A1 and CSNK2B variants in cases of global developmental delay with seizures Nakashima M et al. (2019) No ID
9 Support Okur-Chung neurodevelopmental syndrome in a patient from Spain Martinez-Monseny AF et al. (2020) No Stereotypy
10 Support Overrepresentation of genetic variation in the AnkyrinG interactome is related to a range of neurodevelopmental disorders van der Werf IM et al. (2020) No ASD, epilepsy/seizures
11 Support Dual molecular diagnosis of tricho-rhino-phalangeal syndrome type I and Okur-Chung neurodevelopmental syndrome in one Chinese patient: a case report Xu S et al. (2020) No Impaired social interactions
12 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
13 Recent Recommendation - Dominguez I et al. (2021) No ASD
14 Support - Woodbury-Smith M et al. (2022) Yes -
15 Support - Caefer DM et al. (2022) No -
16 Support - Spataro N et al. (2023) No -
17 Support - Tamam Khalaf et al. (2024) No -
18 Support - Ruohao Wu et al. (2024) No ASD, ADHD, epilepsy/seizures
19 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (47)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.824+2T>C - splice_site_variant De novo - - 27048600 Okur V et al. (2016)
c.973+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.973+1G>C - splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.319C>T p.Arg107Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.571C>T p.Arg191Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.916C>T p.Arg306Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1A>G p.Met1? missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.140G>A p.Arg47Gln missense_variant De novo - - 27048600 Okur V et al. (2016)
c.149A>C p.Tyr50Ser missense_variant De novo - - 27048600 Okur V et al. (2016)
c.116A>G p.Tyr39Cys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.152G>T p.Ser51Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.524A>G p.Asp175Gly missense_variant De novo - - 27048600 Okur V et al. (2016)
c.593A>G p.Lys198Arg missense_variant De novo - - 27048600 Okur V et al. (2016)
c.440G>A p.Cys147Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.140G>A p.Arg47Gln missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.152G>A p.Ser51Asn missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.239G>A p.Arg80His missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.79G>A p.Glu27Lys missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.571C>T p.Arg191Ter stop_gained De novo - - 30655572 Nakashima M et al. (2019)
c.522A>G p.Ile174Met missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.572G>A p.Arg191Gln missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.589T>A p.Phe197Ile missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.593A>G p.Lys198Arg missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.934C>T p.Arg312Trp missense_variant De novo - - 29383814 Owen CI et al. (2018)
c.140G>A p.Arg47Gln missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.151A>C p.Ser51Arg missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.218T>A p.Val73Glu missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.593A>G p.Lys198Arg missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.692C>G p.Pro231Arg missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.935G>A p.Arg312Gln missense_variant De novo - - 29240241 Chiu ATG et al. (2018)
c.593A>G p.Lys198Arg missense_variant De novo - - 36980980 Spataro N et al. (2023)
c.593A>G p.Lys198Arg missense_variant De novo - - 30655572 Nakashima M et al. (2019)
c.154G>A p.Glu52Lys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.538G>A p.Glu180Lys missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.583C>T p.Arg195Ter stop_gained Unknown Not maternal - 33004838 Wang T et al. (2020)
c.466G>C p.Asp156His missense_variant De novo - Simplex 28725024 Trinh J et al. (2017)
c.79G>A p.Glu27Lys missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.149A>G p.Tyr50Cys missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.238C>T p.Arg80Cys missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.479A>G p.His160Arg missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.298A>G p.Ile100Val missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.593A>G p.Lys198Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.149A>G p.Tyr50Cys missense_variant De novo - - 31729156 Martinez-Monseny AF et al. (2020)
c.593A>G p.Lys198Arg missense_variant Familial Paternal Simplex 32746809 Xu S et al. (2020)
c.593A>G p.Lys198Arg missense_variant De novo - Simplex 29619237 Akahira-Azuma M et al. (2018)
c.479A>G p.His160Arg missense_variant De novo - Simplex 32651551 van der Werf IM et al. (2020)
c.593A>G p.Lys198Arg missense_variant De novo - Simplex 32651551 van der Werf IM et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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
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1

Increased from to 1

Krishnan Probability Score

Score 0.44593104918539

Ranking 15118/25841 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 0.99964669784599

Ranking 869/18225 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 0.92437115775386

Ranking 9975/18665 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 0.52346351770168

Ranking 364/20870 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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