CEP152

protein-coding

centrosomal protein 152

Gene summary

This gene encodes a protein that is thought to be involved with centrosome function. Mutations in this gene have been associated with primary microcephaly (MCPH4). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

MANE transcript

NM_001194998.2

Inheritance

ClinVar variants

P:152U:348B:447

Top phenotype

Seckel syndrome 5; Microcephaly 9, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr15:48,712,928-48,811,146

External References & Databases

Ensembl (ENSG00000103995)

Transcript & Mutation Effects

hg38 • Region Span ~98.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly with or without short statureDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100346

Submitter: ClinGen

CEP152 was first reported in relation to autosomal recessive Microcephaly with or without short stature in 2010 (Guernsey et al., PMID: 20598275). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been lumped into one, Microcephaly 9, primary (OMIM: 614852), and Seckel syndrome 5 (OMIM: 613823). Microcephaly with or without short stature is a disorder of fetal brain growth. Individuals have reduced head circumference at birth and variable degrees of intellectual impairment. Clinical features can also include a typical 'bird-head' facial appearance of Seckel syndrome and may include short stature. 7 variants (missense, nonsense, frameshift, splice site) that have been reported in 11 probands in 2 publications (PMIDs: 21131937, 20598275) and are included in this curation. Of note, one reported case was identified to carry two cis homozygous variants in the CEP152 gene. This proband was is included in the curation but not scored. The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by expression studies and a functional alteration study (PMIDs: 21131937, 20598275, 35259752). Cep152 was found to be expressed in developing mice brains and additionally has altered morphology and mitotic function. In summary, CEP152 is definitively associated with autosomal recessive Microcephaly with or without short stature. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations Gene Curation Expert Panel on the meeting date 06/28/22 (SOP Version 8).

Seckel syndrome 5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013443

Submitter: G2P

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

microcephaly 9, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013923

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Seckel syndrome 5; Microcephaly 9, primary, autosomal recessiveAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 20598275; 21131973

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP152 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 985

Inborn genetic diseasesTotal: 205

Microcephaly 9, primary, autosomal recessiveTotal: 160

Seckel syndrome 5Total: 122

not specifiedTotal: 100

CEP152-related disorderTotal: 57

Seckel syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001194998.2. 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			4 clinvar	388 clinvar	1 clinvar	393
missense		2 clinvar	338 clinvar	43 clinvar	4 clinvar	387
nonsense	33 clinvar	19 clinvar	1 clinvar	3 clinvar		56
start loss						0
frameshift	49 clinvar	16 clinvar	3 clinvar	8 clinvar		76
splice donor/acceptor (+/-2bp)	3 clinvar	30 clinvar	2 clinvar			35
Total	85	67	348	442	5	947

Highest pathogenic variant AF is 0.0002837505

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001194998.2	RefSeq	NP_001181927.1	26	MANE Select
ENST00000380950.7	Ensembl	ENSP00000370337.2	26	MANE Select
NM_014985.4	RefSeq	NP_055800.2	25	Standard
ENST00000325747.10	Ensembl	ENSP00000321000.5	24	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
centriole replication
regulation of G2/M transition of mitotic cell cycle
centrosome duplication
ciliary basal body-plasma membrane docking

Molecular Function

protein binding
protein kinase binding

Cellular Component

pericentriolar material
nucleoplasm
centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380950
Coding exons: 26
Length: 98219
Individuals with no LoFs: 124446
Homozygous LoFs: 0
Heterozygous LoFs: 349
Defined: 124795
p: 0.00140

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0279	831	833	0.997	0.0000421	11378
Missense (PolyPhen)		272	275.17	0.98849		3976
Synonymous	-0.329	305	298	1.02	0.0000155	2973
Loss of Function	2.91	56	85.0	0.659	0.00000447	1047

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0027	0.0027	notable
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0.00079	0.00079	rare
East Asian	0.0037	0.0036	notable
Finnish	0.00033	0.00032	rare
European (Non-Finnish)	0.0012	0.0011	notable
South Asian	0.0018	0.0018	notable
Other	0.0017	0.0017	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Necessary for centrosome duplication; the function seems also to involve CEP63, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication (PubMed:26297806). Acts as a molecular scaffold facilitating the interaction of PLK4 and CENPJ, 2 molecules involved in centriole formation (PubMed:21059844, PubMed:20852615). Proposed to snatch PLK4 away from PLK4:CEP92 complexes in early G1 daughter centriole and to reposition PLK4 at the outer boundary of a newly forming CEP152 ring structure (PubMed:24997597). Also plays a key role in deuterosome-mediated centriole amplification in multiciliated that can generate more than 100 centrioles (By similarity). Overexpression of CEP152 can drive amplification of centrioles (PubMed:20852615). {ECO:0000250|UniProtKB:A2AUM9, ECO:0000250|UniProtKB:Q498G2, ECO:0000269|PubMed:20852615, ECO:0000269|PubMed:21059844, ECO:0000269|PubMed:21131973}.;
Disease: DISEASE: Microcephaly 9, primary, autosomal recessive (MCPH9) [MIM:614852]: 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:20598275}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Seckel syndrome 5 (SCKL5) [MIM:613823]: A rare autosomal recessive disorder characterized by proportionate dwarfism of prenatal onset associated with low birth weight, growth retardation, severe microcephaly with a bird-headed like appearance, and mental retardation. {ECO:0000269|PubMed:21131973}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.100

Intolerance Scores

LoFtool: 0.979
RVIS EVS: 0.97
RVIS percentile EVS: 90.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.224

Gene Damage Prediction

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