CDKL5

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

Basic information

Region (hg38): X:18425582-18653629

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 (Definitive), mode of inheritance: XLD
• developmental and epileptic encephalopathy, 2 (Strong), mode of inheritance: XL
• developmental and epileptic encephalopathy, 2 (Definitive), mode of inheritance: XL
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• West syndrome (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.

• not provided (697 variants)
• Developmental and epileptic encephalopathy, 2;Angelman syndrome-like (375 variants)
• Angelman syndrome-like;Developmental and epileptic encephalopathy, 2 (246 variants)
• Developmental and epileptic encephalopathy, 2 (200 variants)
• not specified (117 variants)
• CDKL5 disorder (71 variants)
• Inborn genetic diseases (68 variants)
• Juvenile retinoschisis (60 variants)
• Retinal dystrophy (24 variants)
• Atypical Rett syndrome (21 variants)
• History of neurodevelopmental disorder (10 variants)
• West syndrome (8 variants)
• CDKL5-related condition (8 variants)
• Retinoschisis (7 variants)
• Epileptic encephalopathy (5 variants)
• RS1-related condition (2 variants)
• Seizure (2 variants)
• Rett syndrome (2 variants)
• Early infantile epileptic encephalopathy with suppression bursts (1 variants)
• Angelman syndrome;Developmental and epileptic encephalopathy, 2 (1 variants)
• Abnormal cerebral morphology (1 variants)
• Abnormality of the nervous system (1 variants)
• Intellectual disability (1 variants)
• 8 conditions (1 variants)
• Juvenile retinoschisis;Macular schisis;Peripheral schisis (1 variants)
• Focal epilepsy (1 variants)
• Developmental and epileptic encephalopathy, 1;Developmental and epileptic encephalopathy, 2;Angelman syndrome-like (1 variants)
• Autism (1 variants)
• Nicolaides-Baraitser syndrome (1 variants)
• Developmental and epileptic encephalopathy, 4 (1 variants)
• CDKL5-related disorder (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.

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	1		9	125	18	153
missense	39	60	214	68	19	400
nonsense	58	9	3	2	1	73
start loss						0
frameshift	133	19	4	1		157
inframe indel	1	2	10	1	1	15
splice donor/acceptor (+/-2bp)	26	20	3			49
splice region	5	3	16	23	4	51
non coding	87	60	56	151	50	404
Total	345	170	299	348	89

Highest pathogenic variant AF is 0.00000902

Variants in CDKL5

This is a list of pathogenic ClinVar variants found in the CDKL5 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-18425593-C-G		not specified	Benign (Feb 08, 2013)
X-18425669-C-T		Atypical Rett syndrome	Uncertain significance (Mar 13, 2014)
X-18425684-G-A		not specified	Likely benign (May 18, 2017)
X-18425705-C-T		not specified	Likely benign (Jul 07, 2016)
X-18425708-G-A		not specified	Likely benign (Nov 28, 2017)
X-18425714-A-C			Benign (Mar 03, 2015)
X-18425831-T-C			Likely benign (May 08, 2019)
X-18425834-C-CTT			Likely benign (Sep 20, 2019)
X-18442160-A-G			Benign (Oct 31, 2019)
X-18442467-TTTTTG-T			Benign (Oct 08, 2019)
X-18442467-TTTTTGTTTTGTTTTG-T			Likely benign (Jan 20, 2021)
X-18442467-T-TTTTTG			Benign (Jan 16, 2020)
X-18506832-C-G			Benign (Mar 03, 2015)
X-18506933-A-G		Developmental and epileptic encephalopathy, 2	Pathogenic (Nov 08, 2021)
X-18507079-A-G		not specified	Likely benign (Jun 07, 2017)
X-18507090-T-G		CDKL5-related disorder	Likely benign (Sep 25, 2019)
X-18507092-T-A		not specified	Likely benign (Nov 28, 2017)
X-18507103-A-T		Developmental and epileptic encephalopathy, 2;Angelman syndrome-like	Uncertain significance (Jun 21, 2016)
X-18507109-A-G		Angelman syndrome-like;Developmental and epileptic encephalopathy, 2	Uncertain significance (Dec 15, 2022)
X-18507112-A-G		Developmental and epileptic encephalopathy, 2;Angelman syndrome-like	Uncertain significance (Jul 13, 2023)
X-18507113-T-C		Developmental and epileptic encephalopathy, 2;Angelman syndrome-like	Uncertain significance (Jun 09, 2022)
X-18507117-T-C		Angelman syndrome-like;Developmental and epileptic encephalopathy, 2	Likely benign (May 13, 2019)
X-18507122-T-C		Developmental and epileptic encephalopathy, 2;Angelman syndrome-like	Uncertain significance (Sep 02, 2021)
X-18507125-T-C			Uncertain significance (Nov 12, 2022)
X-18507132-AT-A		Developmental and epileptic encephalopathy, 2	Pathogenic (Mar 13, 2014)

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