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

ENSG00000008086NCBI:6792OMIM:300203HGNC:11411Uniprot:O76039AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

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
  • developmental and epileptic encephalopathy, 2 (Definitive), mode of inheritance: XL
  • CDKL5 disorder (Definitive), mode of inheritance: XL
  • precocious puberty (Limited), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Developmental and epileptic encephalopathy 2XLGeneralGenetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testingNeurologic15499549; 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 (204 variants)
  • Developmental and epileptic encephalopathy, 2;Angelman syndrome-like (95 variants)
  • Developmental and epileptic encephalopathy, 2 (88 variants)
  • Angelman syndrome-like;Developmental and epileptic encephalopathy, 2 (46 variants)
  • Juvenile retinoschisis (19 variants)
  • Atypical Rett syndrome (14 variants)
  • Inborn genetic diseases (14 variants)
  • CDKL5 disorder (9 variants)
  • Retinal dystrophy (9 variants)
  • Retinoschisis (6 variants)
  • CDKL5-related disorder (4 variants)
  • Early infantile epileptic encephalopathy with suppression bursts (2 variants)
  • Epileptic encephalopathy (2 variants)
  • RS1-related disorder (2 variants)
  • Macular schisis;Peripheral schisis;Juvenile retinoschisis (1 variants)
  • Angelman syndrome;Developmental and epileptic encephalopathy, 2 (1 variants)
  • Focal epilepsy (1 variants)
  • West syndrome (1 variants)
  • Intellectual disability (1 variants)
  • 8 conditions (1 variants)
  • Rett syndrome (1 variants)
  • Developmental and epileptic encephalopathy, 4 (1 variants)
  • Seizure (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
clinvar
5
clinvar
149
clinvar
19
clinvar
174
missense
45
clinvar
64
clinvar
247
clinvar
79
clinvar
21
clinvar
456
nonsense
63
clinvar
9
clinvar
3
clinvar
2
clinvar
1
clinvar
78
start loss
0
frameshift
147
clinvar
21
clinvar
5
clinvar
1
clinvar
174
inframe indel
1
clinvar
3
clinvar
10
clinvar
1
clinvar
2
clinvar
17
splice donor/acceptor (+/-2bp)
30
clinvar
18
clinvar
3
clinvar
51
splice region
7
3
19
26
4
59
non coding
94
clinvar
64
clinvar
56
clinvar
205
clinvar
52
clinvar
471
Total 381 179 329 437 95

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 • CDKL5 disorder Benign (Jun 28, 2024)158174
X-18425617-T-A CDKL5-related disorder Likely benign (Jun 11, 2019)3352372
X-18425669-C-T Atypical Rett syndrome • CDKL5 disorder Uncertain significance (Jun 28, 2024)189602
X-18425684-G-A not specified Likely benign (May 18, 2017)509646
X-18425705-C-T not specified Likely benign (Jul 07, 2016)379053
X-18425708-G-A not specified Likely benign (Nov 28, 2017)509242
X-18425714-A-C Benign (Mar 03, 2015)1238572
X-18425831-T-C Likely benign (May 08, 2019)1189327
X-18425834-C-CTT Likely benign (Sep 20, 2019)1194507
X-18442160-A-G Benign (Oct 31, 2019)1222003
X-18442467-TTTTTG-T Benign (Oct 08, 2019)1234180
X-18442467-TTTTTGTTTTGTTTTG-T Likely benign (Jan 20, 2021)1253979
X-18442467-T-TTTTTG Benign (Jan 16, 2020)1258365
X-18506832-C-G Benign (Mar 03, 2015)1229587
X-18506933-A-G Developmental and epileptic encephalopathy, 2 • CDKL5 disorder Pathogenic/Likely pathogenic (Sep 20, 2024)189565
X-18507079-A-G not specified Likely benign (Jun 07, 2017)509992
X-18507090-T-G CDKL5-related disorder Likely benign (Sep 25, 2019)3039544
X-18507092-T-A not specified • CDKL5-related disorder Likely benign (Nov 28, 2017)379694
X-18507103-A-T Developmental and epileptic encephalopathy, 2;Angelman syndrome-like Uncertain significance (Jun 21, 2016)408122
X-18507107-C-G Uncertain significance (Jun 27, 2024)3392751
X-18507109-A-G Developmental and epileptic encephalopathy, 2;Angelman syndrome-like Uncertain significance (Dec 15, 2022)421693
X-18507112-A-G Developmental and epileptic encephalopathy, 2;Angelman syndrome-like Uncertain significance (Jul 13, 2023)2927189
X-18507113-T-C Developmental and epileptic encephalopathy, 2;Angelman syndrome-like Uncertain significance (Jun 09, 2022)2045172
X-18507117-T-C Angelman syndrome-like;Developmental and epileptic encephalopathy, 2 Likely benign (May 13, 2019)1117209
X-18507122-T-C Angelman syndrome-like;Developmental and epileptic encephalopathy, 2 Uncertain significance (Sep 02, 2021)568435

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
CDKL5protein_codingprotein_codingENST00000379989 20228047
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.9990.000678125721111257230.00000795
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense2.742464000.6150.00003236774
Missense in Polyphen1444.310.31596662
Synonymous-0.4981571491.050.00001211987
Loss of Function4.95334.30.08750.00000261613

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.000.00
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.000.00
European (Non-Finnish)0.00002450.0000176
Middle Eastern0.000.00
South Asian0.000.00
Other0.000.00

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

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

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