CDK5RAP2

protein-coding

CDK5 regulatory subunit associated protein 2

Gene summary

This gene encodes a regulator of CDK5 (cyclin-dependent kinase 5) activity. The protein encoded by this gene is localized to the centrosome and Golgi complex, interacts with CDK5R1 and pericentrin (PCNT), plays a role in centriole engagement and microtubule nucleation, and has been linked to primary microcephaly and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

Previous symbols:

MCPH3

MANE transcript

NM_018249.6

Inheritance

ClinVar variants

P:85U:466B:251

Top phenotype

Microcephaly, primary autosomal recessive, 3

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr9:120,388,875-120,580,170

External References & Databases

Ensembl (ENSG00000136861)

Transcript & Mutation Effects

hg38 • Region Span ~191.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive primary microcephalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: ClinGen

Homozygous variants in CDK5RAP2 were first reported individuals with microcephaly in consanguineous family in 2005 (Bond J, et al., PMID: 15793586). Primary microcephaly (OMIM:604804) characterized by a disproportionately small brain and cerebral cortex further characterized by other significant neurological deficits (delayed psychomotor development, moderate learning difficulties, and significant speech delay). Other clinical manifestation as variation were reported: severe sensorineural hearing loss (Pagnamenta et al. (2012), short stature (-6.7 SD), prominent eyes, conical-shaped and widely spaced teeth (Lancaster et al. (2013)). The mechanism of pathogenicity is known to be autosomal recessive loss-of-function. At least nine loss-of-function variants, 3 homozygous and 6 compound heterozygous, have been reported in 6 probands with primary microcephaly, 3 across six publications (PMIDs: 17764569, 15793586, 22887808, 27761245, 23726037, 23995685). This gene-disease relationship is also supported by patient-derived cerebral organoid (PMID: 23995685) and phenotypically compatible mouse model (PMIDs: 20460369). Inducing wildtype CDK5RAP2 expression rescued the developmental abnormality in patient-derived cerebral organoid, which is genetically knock-out for CDK5RAP2 (PMID: 23995685). In summary, CDK5RAP2 is definitively associated with autosomal recessive primary microcephaly, 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This was discussed and approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 01/25/2022 (SOP Version 8).

corpus callosum, agenesis ofLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009022

Submitter: Ambry Genetics

microcephaly 3, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011488

Submitter: G2P

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 3, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011488

Submitter: Ambry Genetics

microcephaly 3, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011488

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly, primary autosomal recessive, 3AR

Manifestation: Audiologic/Otolaryngologic; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: The condition can involve congenital hearing impairment, and early recognition and treatment may improve outcomes, including speech and language development

Refs: 10677332; 15793586; 17764569; 22887808; 23726037; 23995685

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CDK5RAP2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 646

Inborn genetic diseasesTotal: 286

Microcephaly 3, primary, autosomal recessiveTotal: 190

not specifiedTotal: 82

CDK5RAP2-related disorderTotal: 63

Intellectual disabilityTotal: 8

See casesTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018249.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			8 clinvar	184 clinvar	2 clinvar	194
missense	1 clinvar	1 clinvar	439 clinvar	63 clinvar	2 clinvar	506
nonsense	18 clinvar	13 clinvar				31
start loss			1 clinvar			1
frameshift	21 clinvar	15 clinvar	1 clinvar			37
splice donor/acceptor (+/-2bp)	2 clinvar	14 clinvar	17 clinvar			33
Total	42	43	466	247	4	802

Highest pathogenic variant AF is 0.00009417491

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018249.6	RefSeq	NP_060719.4	38	MANE Select
ENST00000349780.9	Ensembl	ENSP00000343818.4	38	MANE Select
NM_001011649.3	RefSeq	NP_001011649.1	37	Standard
NM_001272039.2	RefSeq	NP_001258968.1	35	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

G2/M transition of mitotic cell cycle
establishment of mitotic spindle orientation
microtubule cytoskeleton organization
microtubule bundle formation
chromosome segregation

Molecular Function

protein binding
calmodulin binding
microtubule binding
tubulin binding
protein kinase binding

Cellular Component

pericentriolar material
spindle pole
cytoplasm
Golgi apparatus
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000349780
Coding exons: 38
Length: 191302
Individuals with no LoFs: 125582
Homozygous LoFs: 1
Heterozygous LoFs: 165
Defined: 125748
p: 0.000660

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.370	1005	973	1.03	0.0000540	12482
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00055	0.00052	rare
Ashkenazi Jewish	0.00089	0.00089	rare
East Asian	0.00060	0.00060	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00084	0.00084	rare
South Asian	0.00078	0.00075	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.0847

Intolerance Scores

LoFtool: 0.935
RVIS EVS: -1.95
RVIS percentile EVS: 1.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.639

Gene Damage Prediction

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