CDK8

cyclin dependent kinase 8, the group of Cyclin dependent kinases|Mediator complex

Basic information

Region (hg38): 13:26254104-26420982

Links

ENSG00000132964

∙ NCBI:1024 ∙ OMIM:603184 ∙ HGNC:1779 ∙ Uniprot:P49336 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

intellectual developmental disorder with hypotonia and behavioral abnormalities (Moderate), mode of inheritance: AD
intellectual developmental disorder with hypotonia and behavioral abnormalities (Strong), mode of inheritance: AD
intellectual developmental disorder with hypotonia and behavioral abnormalities (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder with hypotonia and behavioral abnormalities	AD	Cardiovascular	Individuals have been described as affected with a range of cardiovascular anomalies, including potentially occult anomalies requiring interventions, and awareness may allow early diagnosis and management	Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic	30905399

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CDK8 gene.

not_provided (31 variants)
Intellectual_developmental_disorder_with_hypotonia_and_behavioral_abnormalities (30 variants)
Inborn_genetic_diseases (23 variants)
CDK8-related_disorder (7 variants)
Common_atrium (1 variants)
Ventriculomegaly (1 variants)
Ebstein_anomaly (1 variants)
Stillbirth (1 variants)
Intellectual_disability (1 variants)
Abnormal_facial_shape (1 variants)
Congenital_diaphragmatic_hernia (1 variants)
Heart,_malformation_of (1 variants)
Complex_neurodevelopmental_disorder_with_or_without_congenital_anomalies (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDK8 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000001260.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous				4 clinvar		4
missense	9 clinvar	8 clinvar	57 clinvar	3 clinvar		77
nonsense	1 clinvar					1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	10	8	59	7	0

Highest pathogenic variant AF is 0.000003103306

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CDK8	protein_coding	protein_coding	ENST00000381527	13	151100

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.410	0.590	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.68	87	251	0.346	0.0000125	3048
Missense in Polyphen		11	64.52	0.17049		769
Synonymous	0.590	79	86.0	0.919	0.00000433	833
Loss of Function	4.04	7	31.4	0.223	0.00000182	354

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000582	0.0000582
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000356	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000333	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation. {ECO:0000269|PubMed:10993082, ECO:0000269|PubMed:15546612}.;
Pathway: Sterol Regulatory Element-Binding Proteins (SREBP) signalling;H19 action Rb-E2F1 signaling and CDK-β-catenin activity;Developmental Biology;Disease;Signal Transduction;Gene expression (Transcription);estrogen responsive protein efp controls cell cycle and breast tumors growth;Generic Transcription Pathway;Hedgehog;RNA Polymerase II Transcription;Transcriptional regulation of white adipocyte differentiation;SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription;Signaling by NOTCH1;Signaling by NOTCH;IL-7 signaling;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;JAK STAT pathway and regulation;EPO signaling;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Signaling by TGF-beta Receptor Complex;VEGF;Signaling by TGF-beta family members;Diseases of signal transduction;NOTCH1 Intracellular Domain Regulates Transcription (Consensus)

Recessive Scores

pRec: 0.203

Intolerance Scores

loftool: 0.425
rvis_EVS: -0.25
rvis_percentile_EVS: 35.42

Haploinsufficiency Scores

pHI: 0.835
hipred: Y
hipred_score: 0.749
ghis: 0.696

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.539

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Cdk8
Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); embryo phenotype;

Gene ontology

Biological process: transcription initiation from RNA polymerase II promoter;protein phosphorylation;positive regulation of transcription by RNA polymerase II;regulation of cell cycle
Cellular component: nucleus;nucleoplasm;nucleolus;mediator complex;protein-containing complex
Molecular function: protein kinase activity;protein serine/threonine kinase activity;cyclin-dependent protein serine/threonine kinase activity;protein binding;ATP binding;RNA polymerase II CTD heptapeptide repeat kinase activity