CDKL5

cyclin dependent kinase like 5, the group of Cyclin dependent kinases|Cilia and flagella associated

Basic information

Region (hg38): X:18425583-18653629

Previous symbols: [ "STK9" ]

Links

ENSG00000008086 ∙ NCBI:6792 ∙ OMIM:300203 ∙ HGNC:11411 ∙ Uniprot:O76039 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• developmental and epileptic encephalopathy, 2 (Strong), mode of inheritance: XL
• developmental and epileptic encephalopathy, 2 (Definitive), mode of inheritance: XL
• genetic developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• infantile spasms (Supportive), mode of inheritance: AD
• atypical Rett syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy, 2 (Supportive), mode of inheritance: XL
• precocious puberty (Limited), mode of inheritance: XL
• developmental and epileptic encephalopathy, 2 (Definitive), mode of inheritance: XL
• CDKL5 disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 2	XL	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	Neurologic	15499549; 15492925; 15689447; 18266744; 18809835; 18063413; 17993579; 19793311; 19241098; 19396824; 20602487; 21765152; 21770923; 21802232; 22264704; 22430159; 22521361; 22670135; 22678952; 22867051; 23064044
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CDKL5 gene.

• Developmental_and_epileptic_encephalopathy,_2 (936 variants)
• Angelman_syndrome-like (725 variants)
• not_provided (393 variants)
• CDKL5_disorder (312 variants)
• not_specified (105 variants)
• Inborn_genetic_diseases (84 variants)
• Atypical_Rett_syndrome (43 variants)
• CDKL5-related_disorder (32 variants)
• Rett_syndrome (15 variants)
• West_syndrome (7 variants)
• Seizure (6 variants)
• Epileptic_encephalopathy (6 variants)
• History_of_neurodevelopmental_disorder (5 variants)
• Intellectual_disability (3 variants)
• Autism (3 variants)
• Developmental_and_epileptic_encephalopathy (2 variants)
• Developmental_delay (2 variants)
• Stereotypic_movement_disorder (1 variants)
• Abnormal_cerebral_morphology (1 variants)
• Infantile_spasms (1 variants)
• Delayed_speech_and_language_development (1 variants)
• Focal_epilepsy (1 variants)
• Angelman_syndrome (1 variants)
• Bruxism (1 variants)
• Generalized_hypotonia (1 variants)
• Craniosynostosis_syndrome (1 variants)
• Global_developmental_delay (1 variants)
• Stereotypical_hand_wringing (1 variants)
• Abnormality_of_the_nervous_system (1 variants)
• Stereotypical_body_rocking (1 variants)
• Developmental_and_epileptic_encephalopathy,_4 (1 variants)
• Developmental_and_epileptic_encephalopathy,_1 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDKL5 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001323289.2. 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	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	1	6	157	13	179
missense	43	90	290	68	20	511
nonsense	81	21				102
start loss						0
frameshift	191	69				260
splice donor/acceptor (+/-2bp)	43	27	3			73
Total	360	208	299	225	33

Highest pathogenic variant AF is 0.000003642178

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CDKL5	protein_coding	protein_coding	ENST00000379989	20	228047

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.000678	125721	1	1	125723	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.74	246	400	0.615	0.0000323	6774
Missense in Polyphen		14	44.31	0.31596		662
Synonymous	-0.498	157	149	1.05	0.0000121	1987
Loss of Function	4.95	3	34.3	0.0875	0.00000261	613

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000245	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Mediates phosphorylation of MECP2 (PubMed:15917271, PubMed:16935860). May regulate ciliogenesis (PubMed:29420175). {ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16935860, ECO:0000269|PubMed:29420175}.
• Disease: DISEASE: Note=Chromosomal aberrations involving CDKL5 are found in patients manifesting early-onset seizures and spams and psychomotor impairment. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15).; DISEASE: Epileptic encephalopathy, early infantile, 2 (EIEE2) [MIM:300672]: A severe form of epilepsy characterized by seizures or spasms beginning in infancy. Patients with epileptic encephalopathy early infantile type 2 manifest features resembling Rett syndrome such as microcephaly, lack of speech development, stereotypic hand movements. However, EIEE2 and Rett syndrome are considered two distinct entities. {ECO:0000269|PubMed:12736870, ECO:0000269|PubMed:15492925, ECO:0000269|PubMed:15499549, ECO:0000269|PubMed:15689447, ECO:0000269|PubMed:15917271, ECO:0000269|PubMed:16015284, ECO:0000269|PubMed:16611748, ECO:0000269|PubMed:16935860, ECO:0000269|PubMed:17993579, ECO:0000269|PubMed:18790821, ECO:0000269|PubMed:18809835, ECO:0000269|PubMed:19241098, ECO:0000269|PubMed:19253388, ECO:0000269|PubMed:23662938, ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:24564546, ECO:0000269|PubMed:26993267, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Brain-Derived Neurotrophic Factor (BDNF) signaling pathway (Consensus)

Intolerance Scores

• loftool: 0.128
• rvis_EVS: -0.67
• rvis_percentile_EVS: 15.86

Haploinsufficiency Scores

• pHI: 0.498
• hipred: Y
• hipred_score: 0.853
• ghis: 0.572

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.924

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cdkl5
• 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); vision/eye phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: neuron migration;protein phosphorylation;positive regulation of GTPase activity;positive regulation of axon extension;protein autophosphorylation;regulation of dendrite development;positive regulation of dendrite morphogenesis;regulation of cell cycle;positive regulation of dendritic spine development;regulation of postsynapse organization;regulation of cilium assembly
• Cellular component: nucleus;nucleoplasm;centrosome;cytosol;ruffle membrane;dendrite cytoplasm;ciliary basal body;dendritic growth cone;perinuclear region of cytoplasm;ciliary tip;glutamatergic synapse;postsynaptic density, intracellular component
• Molecular function: protein kinase activity;protein serine/threonine kinase activity;cyclin-dependent protein serine/threonine kinase activity;ATP binding;kinase activity;Rac GTPase binding