CSNK2A1

protein-coding

casein kinase 2 alpha 1

Gene summary

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. Multiple transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Apr 2018]

MANE transcript

NM_177559.3

Inheritance

ClinVar variants

P:91U:89B:28

Top phenotype

Okur-Chung neurodevelopmental syndrome

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr20:472,498-543,835

External References & Databases

Ensembl (ENSG00000101266)

Transcript & Mutation Effects

hg38 • Region Span ~71.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Okur-Chung neurodevelopmental syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014893

Submitter: Illumina

Okur-Chung neurodevelopmental syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014893

Submitter: Labcorp Genetics (formerly Invitae)

Okur-Chung neurodevelopmental syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014893

Submitter: G2P

Okur-Chung neurodevelopmental syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014893

Submitter: Ambry Genetics

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Variants in *CSNK2A1* were first reported in relation to an autosomal dominant form of syndromic intellectual disability, also known as Okur-Chung neurodevelopmental disorder, in 2016 (Okur et al., PMID: 27048600). Clinical features in reported probands include global developmental delay, intellectual disability, abnormal facial shape, short stature, behavioral abnormalities, hypotonia, sleep disturbance, seizures, ataxia, as well as brain, heart, skin, and pituitary gland abnormalities. Most reported variants are missense, and the rest are nonsense, splice and frameshift variants; the majority are *de novo*. Fourteen unique missense and two protein truncating variants that have been reported in six publications (PMIDs: 27048600, 28725024, 29383814, 30655572, 31729156, 34038195) are included in this curation. Though functional data is available to support many of the variants, it has been scored as experimental evidence rather than at the level of each individual variant. More evidence is available in the literature (PMID: 2961923), but the maximum score for genetic evidence has been reached. Of note, five of the reported missense variants are recurrent. This gene-disease relationship is also supported by experimental evidence, including functional studies, biochemical function, protein interaction and a mouse model. *CSNK2A1* encodes CK2α, a serine/threonine protein kinase. Variants in *CSNK2A1* have been shown to cause a decrease in the kinase activity of the CK2α protein and changes in the alpha subunit’s subcellular localization (PMID: 33944995). CK2α interacts with the CK2β subunit encoded by *CSNK2B*, which is also implicated in syndromic intellectual disability (Poirier-Bienvenu neurodevelopmental syndrome). In summary, there is definitive evidence supporting the relationship between *CSNK2A1* and autosomal dominant syndromic intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on June 15, 2022 (SOP Version 9).

Clinical Genomic Database (CGD)

Okur-Chung neurodevelopmental syndromeAD

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Among other findings, individuals have been described with hypogammaglobulinemia and mild IgA or IgG deficiency and awareness may allow surveillance and management related to potential infectious sequelae

Refs: 27048600; 28725024; 29240241; 29383814; 29619237

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CSNK2A1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 148

Okur-Chung neurodevelopmental syndromeTotal: 85

Inborn genetic diseasesTotal: 29

not specifiedTotal: 25

CSNK2A1-related disorderTotal: 19

Neurodevelopmental disorderTotal: 1

EpilepsyTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177559.3. 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				13 clinvar	1 clinvar	14
missense	15 clinvar	34 clinvar	75 clinvar	14 clinvar		138
nonsense	8 clinvar	12 clinvar	4 clinvar			24
start loss	1 clinvar		1 clinvar			2
frameshift	6 clinvar	7 clinvar	4 clinvar			17
splice donor/acceptor (+/-2bp)	5 clinvar	3 clinvar	5 clinvar			13
Total	35	56	89	27	1	208

Highest pathogenic variant AF is 0.000006589525

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 97 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_177559.3	RefSeq	NP_808227.1	12	MANE Select
ENST00000217244.9	Ensembl	ENSP00000217244.3	12	MANE Select
NM_001362770.2	RefSeq	NP_001349699.1	12	Standard
NM_001362771.2	RefSeq	NP_001349700.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Adherens junction - Homo sapiens (human)
Ribosome biogenesis in eukaryotes - Homo sapiens (human)
Mitophagy - animal - Homo sapiens (human)
Measles - Homo sapiens (human)
Wnt signaling pathway - Homo sapiens (human)

Biological Process

protein phosphorylation
apoptotic process
cell cycle
signal transduction
positive regulation of cell population proliferation

Molecular Function

protein serine/threonine kinase activity
protein binding
ATP binding
kinase activity
identical protein binding

Cellular Component

nucleus
nucleoplasm
cytosol
plasma membrane
protein kinase CK2 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217244
Coding exons: 12
Length: 65350
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125744
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	66	221	0.298	0.0000118	2554
Missense (PolyPhen)		11	96.258	0.11428		1140
Synonymous	0.343	75	78.9	0.951	0.00000443	716
Loss of Function	4.47	4	30.8	0.130	0.00000214	302

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalytic subunit of a constitutively active serine/threonine-protein kinase complex that phosphorylates a large number of substrates containing acidic residues C-terminal to the phosphorylated serine or threonine. Regulates numerous cellular processes, such as cell cycle progression, apoptosis and transcription, as well as viral infection. May act as a regulatory node which integrates and coordinates numerous signals leading to an appropriate cellular response. During mitosis, functions as a component of the p53/TP53-dependent spindle assembly checkpoint (SAC) that maintains cyclin-B-CDK1 activity and G2 arrest in response to spindle damage. Also required for p53/TP53-mediated apoptosis, phosphorylating 'Ser-392' of p53/TP53 following UV irradiation. Can also negatively regulate apoptosis. Phosphorylates the caspases CASP9 and CASP2 and the apoptotic regulator NOL3. Phosphorylation protects CASP9 from cleavage and activation by CASP8, and inhibits the dimerization of CASP2 and activation of CASP8. Regulates transcription by direct phosphorylation of RNA polymerases I, II, III and IV. Also phosphorylates and regulates numerous transcription factors including NF-kappa-B, STAT1, CREB1, IRF1, IRF2, ATF1, SRF, MAX, JUN, FOS, MYC and MYB. Phosphorylates Hsp90 and its co-chaperones FKBP4 and CDC37, which is essential for chaperone function. Regulates Wnt signaling by phosphorylating CTNNB1 and the transcription factor LEF1. Acts as an ectokinase that phosphorylates several extracellular proteins. During viral infection, phosphorylates various proteins involved in the viral life cycles of EBV, HSV, HBV, HCV, HIV, CMV and HPV. Phosphorylates PML at 'Ser-565' and primes it for ubiquitin- mediated degradation. Plays an important role in the circadian clock function by phosphorylating ARNTL/BMAL1 at 'Ser-90' which is pivotal for its interaction with CLOCK and which controls CLOCK nuclear entry (PubMed:11239457, PubMed:11704824, PubMed:16193064, PubMed:19188443, PubMed:20625391, PubMed:22406621). Phosphorylates CCAR2 at 'Thr-454' in gastric carcinoma tissue (PubMed:24962073). {ECO:0000269|PubMed:11239457, ECO:0000269|PubMed:11704824, ECO:0000269|PubMed:16193064, ECO:0000269|PubMed:19188443, ECO:0000269|PubMed:20625391, ECO:0000269|PubMed:22406621, ECO:0000269|PubMed:24962073}.;
Disease: DISEASE: Okur-Chung neurodevelopmental syndrome (OCNDS) [MIM:617062]: An autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral problems, hypotonia, speech problems, microcephaly, pachygyria and variable dysmorphic features. {ECO:0000269|PubMed:27048600}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.796

Intolerance Scores

LoFtool: 0.182
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.877

Gene Damage Prediction

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