CEP135

protein-coding

centrosomal protein 135

Gene summary

This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

Previous symbols:

KIAA0635
CEP4

MANE transcript

NM_025009.5

Inheritance

ClinVar variants

P:68U:246B:141

Top phenotype

Microcephaly 8, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr4:55,948,871-56,033,361

External References & Databases

Ensembl (ENSG00000174799)

Transcript & Mutation Effects

hg38 • Region Span ~84.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 8, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013849

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 8, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013849

Submitter: G2P

Clinical Genomic Database (CGD)

Microcephaly 8, 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: 22521416

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP135 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 402

Inborn genetic diseasesTotal: 171

Microcephaly 8, primary, autosomal recessiveTotal: 39

not specifiedTotal: 38

CEP135-related disorderTotal: 29

Auditory neuropathy spectrum disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025009.5. 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	103 clinvar	2 clinvar	109
missense		1 clinvar	233 clinvar	34 clinvar	2 clinvar	270
nonsense	13 clinvar	12 clinvar	3 clinvar			28
start loss						0
frameshift	21 clinvar	10 clinvar				31
splice donor/acceptor (+/-2bp)	1 clinvar	10 clinvar	6 clinvar			17
Total	35	33	246	137	4	455

Highest pathogenic variant AF is 0.00008490732

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025009.5	RefSeq	NP_079285.2	24	MANE Select
ENST00000257287.5	Ensembl	ENSP00000257287.3	24	MANE Select
ENST00000422247.6	Ensembl	ENSP00000412799.2	5	Standard
ENST00000422247.7	Ensembl	ENSP00000412799.2	5	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
centriole-centriole cohesion
ciliary basal body-plasma membrane docking

Molecular Function

protein binding
protein C-terminus binding

Cellular Component

centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000257287
Coding exons: 24
Length: 84493
Individuals with no LoFs: 125511
Homozygous LoFs: 0
Heterozygous LoFs: 237
Defined: 125748
p: 0.000943

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0804	565	570	0.991	0.0000298	7475
Missense (PolyPhen)		175	181.33	0.96512		2513
Synonymous	0.804	180	194	0.927	0.00000943	2027
Loss of Function	2.87	46	72.4	0.635	0.00000453	883

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0037	0.0037	notable
Latino/Admixed American	0.00066	0.00058	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.0020	0.0020	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00073	0.00071	rare
South Asian	0.0010	0.00098	notable
Other	0.00051	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in early centriole assembly/duplication/biogenesis/formation/. Required for centriole elongation. Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner. {ECO:0000269|PubMed:27185865}.;
Disease: DISEASE: Microcephaly 8, primary, autosomal recessive (MCPH8) [MIM:614673]: 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:22521416}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.117

Intolerance Scores

LoFtool: 0.995
RVIS EVS: 0.43
RVIS percentile EVS: 77.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.865

Gene Damage Prediction

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