CDK5RAP2

CDK5 regulatory subunit associated protein 2

Basic information

Region (hg38): 9:120388875-120580170

Previous symbols: [ "MCPH3" ]

Links

ENSG00000136861 ∙ NCBI:55755 ∙ OMIM:608201 ∙ HGNC:18672 ∙ Uniprot:Q96SN8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephaly 3, primary, autosomal recessive (Moderate), mode of inheritance: AR
• microcephaly 3, primary, autosomal recessive (Strong), mode of inheritance: AR
• microcephaly 3, primary, autosomal recessive (Strong), mode of inheritance: AR
• autosomal recessive primary microcephaly (Supportive), mode of inheritance: AR
• corpus callosum, agenesis of (Limited), mode of inheritance: AR
• autosomal recessive primary microcephaly (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly, primary autosomal recessive, 3	AR	Audiologic/Otolaryngologic	The condition can involve congenital hearing impairment, and early recognition and treatment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Neurologic	10677332; 15793586; 17764569; 22887808; 23726037; 23995685

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CDK5RAP2 gene.

• Microcephaly 3, primary, autosomal recessive (15 variants)
• not provided (13 variants)
• CDK5RAP2-related disorder (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CDK5RAP2 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			7	126	1	134
missense			274	12	5	291
nonsense	13	8				21
start loss			1			1
frameshift	10	4	1			15
inframe indel						0
splice donor/acceptor (+/-2bp)	2	5	1			8
splice region			14	26		40
non coding		1	23	108	70	202
Total	25	18	307	246	76

Highest pathogenic variant AF is 0.0000657

Variants in CDK5RAP2

This is a list of pathogenic ClinVar variants found in the CDK5RAP2 region.

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

Position	Type	Phenotype	Significance	ClinVar
9-120388905-T-A		Microcephaly 3, primary, autosomal recessive	Uncertain significance (Jan 15, 2018)
9-120388925-G-A		Microcephaly 3, primary, autosomal recessive	Uncertain significance (Jan 12, 2018)
9-120388972-C-T		Microcephaly 3, primary, autosomal recessive	Benign (Jan 13, 2018)
9-120389025-G-C		Microcephaly 3, primary, autosomal recessive	Uncertain significance (Jan 12, 2018)
9-120389189-G-A		Microcephaly 3, primary, autosomal recessive	Uncertain significance (Jan 13, 2018)
9-120389206-A-T		Microcephaly 3, primary, autosomal recessive	Uncertain significance (Jan 13, 2018)
9-120389269-T-C		Microcephaly 3, primary, autosomal recessive • not specified • CDK5RAP2-related disorder	Conflicting classifications of pathogenicity (Dec 14, 2023)
9-120389271-G-A		Inborn genetic diseases	Uncertain significance (Feb 11, 2022)
9-120389277-C-G		not specified	Uncertain significance (Dec 04, 2014)
9-120389291-AG-A		Inborn genetic diseases	Uncertain significance (May 18, 2021)
9-120389292-G-C		Inborn genetic diseases	Uncertain significance (Jan 27, 2021)
9-120389297-G-A			Likely benign (Apr 29, 2023)
9-120389310-A-G			Likely benign (Apr 14, 2023)
9-120389372-G-A			Likely benign (Aug 15, 2019)
9-120389401-A-G			Benign (Jun 16, 2018)
9-120389744-C-T			Likely benign (Aug 10, 2023)
9-120389763-C-A			Uncertain significance (Aug 15, 2022)
9-120389782-C-T		CDK5RAP2-related disorder	Uncertain significance (Apr 23, 2022)
9-120389787-A-T		Microcephaly 3, primary, autosomal recessive	Likely pathogenic (Mar 17, 2024)
9-120389802-A-C			Likely benign (Aug 11, 2022)
9-120389821-C-G		not specified • Microcephaly 3, primary, autosomal recessive	Benign (Jul 14, 2021)
9-120389963-A-C			Benign (Jun 16, 2018)
9-120389982-G-A			Likely benign (Jul 31, 2018)
9-120390029-T-C			Likely benign (Apr 07, 2019)
9-120394196-C-T			Likely benign (Nov 10, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CDK5RAP2	protein_coding	protein_coding	ENST00000349780	38	191302

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.62e-23	1.00	125582	1	165	125748	0.000660

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.370	1005	973	1.03	0.0000540	12482
Missense in Polyphen		195	212.82	0.91627		2916
Synonymous	0.350	370	379	0.977	0.0000211	3505
Loss of Function	4.41	54	102	0.529	0.00000533	1281

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000922	0.000922
Ashkenazi Jewish	0.000893	0.000893
East Asian	0.000602	0.000598
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000840	0.000835
Middle Eastern	0.000602	0.000598
South Asian	0.000784	0.000752
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Potential regulator of CDK5 activity via its interaction with CDK5R1. Negative regulator of centriole disengagement (licensing) which maintains centriole engagement and cohesion. Involved in regulation of mitotic spindle orientation (By similarity). Plays a role in the spindle checkpoint activation by acting as a transcriptional regulator of both BUBR1 and MAD2 promoter. Together with EB1/MAPRE1, may promote microtubule polymerization, bundle formation, growth and dynamics at the plus ends. Regulates centrosomal maturation by recruitment of the gamma-tubulin ring complex (gamma-TuRC) onto centrosomes (PubMed:26485573). In complex with PDE4DIP isoform 13/MMG8/SMYLE, MAPRE1 and AKAP9, contributes to microtubules nucleation and extension from the centrosome to the cell periphery (PubMed:29162697). Required for the recruitment of AKAP9 to centrosomes (PubMed:29162697). Plays a role in neurogenesis (By similarity). {ECO:0000250|UniProtKB:Q8K389, ECO:0000269|PubMed:17959831, ECO:0000269|PubMed:18042621, ECO:0000269|PubMed:19282672, ECO:0000269|PubMed:19553473, ECO:0000269|PubMed:26485573, ECO:0000269|PubMed:29162697}.
• Disease: DISEASE: Microcephaly 3, primary, autosomal recessive (MCPH3) [MIM:604804]: A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals are mentally retarded. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. {ECO:0000269|PubMed:15793586}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Regulation of PLK1 Activity at G2/M Transition;Recruitment of mitotic centrosome proteins and complexes;Loss of Nlp from mitotic centrosomes;Loss of proteins required for interphase microtubule organization from the centrosome;Centrosome maturation;AURKA Activation by TPX2;G2/M Transition;Mitotic G2-G2/M phases;Recruitment of NuMA to mitotic centrosomes;Mitotic Prometaphase;M Phase;Cell Cycle;Cell Cycle, Mitotic;Anchoring of the basal body to the plasma membrane;Cilium Assembly;Organelle biogenesis and maintenance (Consensus)

Recessive Scores

• pRec: 0.0847

Intolerance Scores

• loftool: 0.935
• rvis_EVS: -1.95
• rvis_percentile_EVS: 1.87

Haploinsufficiency Scores

• pHI: 0.0378
• hipred: N
• hipred_score: 0.481
• ghis: 0.477

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.639

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cdk5rap2
• Phenotype: hematopoietic system 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); reproductive system phenotype; neoplasm; 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; immune system phenotype; cellular phenotype; skeleton phenotype; growth/size/body region 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); craniofacial phenotype

Gene ontology

• Biological process: G2/M transition of mitotic cell cycle;establishment of mitotic spindle orientation;microtubule cytoskeleton organization;microtubule bundle formation;chromosome segregation;centrosome cycle;centriole replication;brain development;regulation of G2/M transition of mitotic cell cycle;neurogenesis;microtubule organizing center organization;positive regulation of microtubule polymerization;regulation of neuron differentiation;negative regulation of neuron differentiation;positive regulation of transcription, DNA-templated;negative regulation of centriole replication;regulation of mitotic cell cycle spindle assembly checkpoint;ciliary basal body-plasma membrane docking
• Cellular component: pericentriolar material;spindle pole;cytoplasm;Golgi apparatus;centrosome;cytosol;cytoskeleton;microtubule;gamma-tubulin ring complex;cell junction;microtubule plus-end;perinuclear region of cytoplasm;extracellular exosome;mitotic spindle pole
• Molecular function: protein binding;calmodulin binding;microtubule binding;tubulin binding;protein kinase binding;gamma-tubulin binding;transcription regulatory region DNA binding