CDK5
cyclin dependent kinase 5, the group of Cyclin dependent kinases
Basic information
Region (hg38): 7:151053814-151057897
Links
Phenotypes
GenCC
Source:
- lissencephaly 7 with cerebellar hypoplasia (Limited), mode of inheritance: AR
- lissencephaly 7 with cerebellar hypoplasia (Limited), mode of inheritance: AR
- lissencephaly 7 with cerebellar hypoplasia (Strong), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Lissencephaly 7 with cerebellar hypoplasia | AR | General | Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing | Craniofacial; Musculoskeletal; Neurologic | 25560765 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (37 variants)
- Inborn genetic diseases (5 variants)
- not specified (2 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDK5 gene is commonly pathogenic or not.
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.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 11 | 11 | ||||
| missense | 7 | |||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| inframe indel | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| splice region ? | 1 | 1 | 2 | 4 | ||
| non coding ? | 12 | 18 | ||||
| Total | 0 | 0 | 7 | 23 | 6 |
Variants in CDK5
This is a list of pathogenic ClinVar variants found in the CDK5 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 7-151054004-G-A | CDK5-related disorder | Benign (May 28, 2019) | ||
| 7-151054051-C-T | CDK5-related disorder | Likely benign (May 16, 2023) | ||
| 7-151054060-T-G | Likely benign (Dec 31, 2019) | |||
| 7-151054192-C-T | Likely benign (Mar 20, 2023) | |||
| 7-151054250-C-T | Uncertain significance (Dec 06, 2022) | |||
| 7-151054251-G-A | Likely benign (Mar 29, 2018) | |||
| 7-151054275-C-T | Likely benign (Mar 04, 2022) | |||
| 7-151054284-C-A | not specified | Likely benign (Dec 02, 2021) | ||
| 7-151054285-G-A | Uncertain significance (Aug 04, 2023) | |||
| 7-151054397-C-A | Benign (Jan 17, 2022) | |||
| 7-151054428-T-C | not specified | Uncertain significance (Aug 31, 2023) | ||
| 7-151054447-G-A | Likely benign (Aug 28, 2023) | |||
| 7-151054447-G-C | Likely benign (Jan 29, 2024) | |||
| 7-151054474-G-A | not specified | Conflicting classifications of pathogenicity (Mar 21, 2023) | ||
| 7-151054475-G-A | Likely benign (Jul 06, 2018) | |||
| 7-151054483-G-A | Likely benign (Aug 25, 2023) | |||
| 7-151055013-G-T | Likely benign (Dec 20, 2023) | |||
| 7-151055065-G-A | Likely benign (Nov 26, 2022) | |||
| 7-151055109-CAG-C | Benign (Jan 22, 2024) | |||
| 7-151055111-G-A | Likely benign (Dec 30, 2021) | |||
| 7-151055263-C-G | Likely benign (Jun 24, 2023) | |||
| 7-151055276-C-T | Lissencephaly 7 with cerebellar hypoplasia | Pathogenic (Mar 01, 2015) | ||
| 7-151055308-G-A | Likely benign (Aug 17, 2018) | |||
| 7-151055315-G-A | not specified | Uncertain significance (Oct 06, 2022) | ||
| 7-151055383-AC-A | Benign (Jan 19, 2024) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CDK5 | protein_coding | protein_coding | ENST00000485972 | 12 | 4719 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.139 | 0.860 | 124648 | 0 | 7 | 124655 | 0.0000281 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 3.07 | 56 | 168 | 0.334 | 0.00000939 | 1876 |
| Missense in Polyphen | 22 | 80.58 | 0.27302 | 900 | ||
| Synonymous | 0.0288 | 75 | 75.3 | 0.996 | 0.00000492 | 552 |
| Loss of Function | 2.94 | 5 | 18.7 | 0.267 | 9.47e-7 | 211 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00 | 0.00 |
| Ashkenazi Jewish | 0.0000994 | 0.0000993 |
| East Asian | 0.00 | 0.00 |
| Finnish | 0.0000929 | 0.0000928 |
| European (Non-Finnish) | 0.0000355 | 0.0000354 |
| Middle Eastern | 0.00 | 0.00 |
| South Asian | 0.00 | 0.00 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3- type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and CDK5R2 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma- dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin- dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1- EPHA4 signaling. The complex p35/CDK5 participates in the regulation of the circadian clock by modulating the function of CLOCK protein: phosphorylates CLOCK at 'Thr-451' and 'Thr-461' and regulates the transcriptional activity of the CLOCK-ARNTL/BMAL1 heterodimer in association with altered stability and subcellular distribution. {ECO:0000269|PubMed:12393264, ECO:0000269|PubMed:12691662, ECO:0000269|PubMed:15992363, ECO:0000269|PubMed:17009320, ECO:0000269|PubMed:17121855, ECO:0000269|PubMed:17591690, ECO:0000269|PubMed:17611284, ECO:0000269|PubMed:17671990, ECO:0000269|PubMed:18042622, ECO:0000269|PubMed:19081376, ECO:0000269|PubMed:19693690, ECO:0000269|PubMed:20061803, ECO:0000269|PubMed:20213743, ECO:0000269|PubMed:20826806, ECO:0000269|PubMed:21209322, ECO:0000269|PubMed:21220307, ECO:0000269|PubMed:21442427, ECO:0000269|PubMed:21465480, ECO:0000269|PubMed:21499257, ECO:0000269|PubMed:24235147, ECO:0000269|PubMed:9822744}.;
- Disease
- DISEASE: Lissencephaly 7, with cerebellar hypoplasia (LIS7) [MIM:616342]: A form of lissencephaly, a disorder of cortical development characterized by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six- layered cortex. LIS7 patients manifest lack of psychomotor development, facial dysmorphism, arthrogryposis, and early-onset intractable seizures resulting in death in infancy. {ECO:0000269|PubMed:25560765}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Alzheimer,s disease - Homo sapiens (human);Axon guidance - Homo sapiens (human);Cocaine addiction - Homo sapiens (human);Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics;miRNA Regulation of DNA Damage Response;Nicotine Activity on Dopaminergic Neurons;Alzheimers Disease;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;ATM Signaling Network in Development and Disease;DNA Damage Response;Developmental Biology;Signaling by GPCR;Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models;Neurodegenerative Diseases;Disease;Signal Transduction;Gene expression (Transcription);bioactive peptide induced signaling pathway;fosb gene expression and drug abuse;regulation of ck1/cdk5 by type 1 glutamate receptors;estrogen responsive protein efp controls cell cycle and breast tumors growth;lissencephaly gene (lis1) in neuronal migration and development;deregulation of cdk5 in alzheimers disease;phosphorylation of mek1 by cdk5/p35 down regulates the map kinase pathway;rac1 cell motility signaling pathway;Generic Transcription Pathway;GPCR Dopamine D1like receptor;Factors involved in megakaryocyte development and platelet production;RNA Polymerase II Transcription;AndrogenReceptor;DARPP-32 events;IL-7 signaling;Activated NTRK2 signals through CDK5;Signaling by NTRK2 (TRKB);Signaling by NTRKs;EGFR1;Glucocorticoid receptor regulatory network;Hemostasis;Semaphorin interactions;JAK STAT pathway and regulation;EPO signaling;Regulation of TP53 Activity through Phosphorylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Opioid Signalling;G alpha (i) signalling events;Axon guidance;Leptin;CRMPs in Sema3A signaling;Signaling by Receptor Tyrosine Kinases;VEGF;GPCR downstream signalling;Reelin signaling pathway;Trk receptor signaling mediated by the MAPK pathway;Lissencephaly gene (LIS1) in neuronal migration and development;EPHA forward signaling
(Consensus)
Recessive Scores
- pRec
- 0.566
Intolerance Scores
- loftool
- rvis_EVS
- -0.03
- rvis_percentile_EVS
- 51.04
Haploinsufficiency Scores
- pHI
- 0.533
- hipred
- Y
- hipred_score
- 0.831
- ghis
- 0.644
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.995
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Medium |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cdk5
- Phenotype
- integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); 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); normal phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- cdk5
- Affected structure
- Rohon-Beard neuron
- Phenotype tag
- abnormal
- Phenotype quality
- displaced to
Gene ontology
- Biological process
- microtubule cytoskeleton organization;neuron migration;synaptic transmission, dopaminergic;protein phosphorylation;intracellular protein transport;nucleocytoplasmic transport;mitochondrion organization;cell cycle;cell-matrix adhesion;chemical synaptic transmission;axonogenesis;synapse assembly;skeletal muscle tissue development;motor neuron axon guidance;cell population proliferation;visual learning;response to wounding;Schwann cell development;synaptic vesicle exocytosis;regulation of macroautophagy;phosphorylation;histone phosphorylation;peptidyl-serine phosphorylation;peptidyl-threonine phosphorylation;sensory perception of pain;cerebellar cortex formation;hippocampus development;layer formation in cerebral cortex;central nervous system neuron development;corpus callosum development;neuron differentiation;regulation of cell migration;negative regulation of axon extension;cortical actin cytoskeleton organization;neuron projection development;negative regulation of protein ubiquitination;negative regulation of synaptic plasticity;positive regulation of protein binding;receptor catabolic process;positive regulation of glial cell apoptotic process;synaptic transmission, glutamatergic;protein localization to synapse;serine phosphorylation of STAT protein;regulation of apoptotic process;receptor clustering;positive regulation of neuron apoptotic process;negative regulation of cell cycle;positive regulation of protein kinase activity;negative regulation of proteolysis;negative regulation of transcription, DNA-templated;protein autophosphorylation;negative regulation of protein export from nucleus;behavioral response to cocaine;regulation of synaptic plasticity;synaptic vesicle endocytosis;synaptic vesicle transport;rhythmic process;axon extension;oligodendrocyte differentiation;dendrite morphogenesis;cell division;neuron apoptotic process;regulation of synaptic transmission, glutamatergic;excitatory postsynaptic potential;regulation of dendritic spine morphogenesis;calcium ion import;regulation of cell cycle arrest;positive regulation of protein targeting to membrane;synapse pruning;induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration;negative regulation of neuron death;regulation of protein localization to plasma membrane;regulation of synaptic vesicle recycling;cellular response to amyloid-beta;positive regulation of actin cytoskeleton reorganization;positive regulation of signaling receptor activity
- Cellular component
- nucleus;nucleoplasm;cytoplasm;cytosol;microtubule;plasma membrane;postsynaptic density;membrane;protein kinase 5 complex;lamellipodium;cell junction;filopodium;axon;dendrite;growth cone;neuromuscular junction;neuron projection;neuronal cell body;perikaryon;postsynaptic membrane;Schaffer collateral - CA1 synapse;presynapse;glutamatergic synapse
- Molecular function
- p53 binding;protein kinase activity;protein serine/threonine kinase activity;cyclin-dependent protein serine/threonine kinase activity;ErbB-2 class receptor binding;protein binding;ATP binding;microtubule binding;kinase activity;protein kinase binding;acetylcholine receptor activator activity;ErbB-3 class receptor binding;ephrin receptor binding;tau protein binding;tau-protein kinase activity;Hsp90 protein binding;voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels