CEP63

protein-coding

centrosomal protein 63

Gene summary

This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001353108.3

Inheritance

ClinVar variants

P:40U:167B:69

Top phenotype

Seckel syndrome 6

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr3:134,485,699-134,587,789

External References & Databases

Ensembl (ENSG00000182923)

Transcript & Mutation Effects

hg38 • Region Span ~102.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Seckel syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013871

Submitter: Labcorp Genetics (formerly Invitae)

Seckel syndrome 6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013871

Submitter: G2P

Seckel syndrome 6MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013871

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Seckel syndrome 6AR

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: 21983783

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP63 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 235

Inborn genetic diseasesTotal: 89

not specifiedTotal: 35

Seckel syndrome 6Total: 21

CEP63-related disorderTotal: 9

Developmental dyslexiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001353108.3. 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			3 clinvar	55 clinvar	1 clinvar	59
missense			152 clinvar	11 clinvar	2 clinvar	165
nonsense	10 clinvar	5 clinvar	3 clinvar			18
start loss						0
frameshift	9 clinvar	5 clinvar	4 clinvar			18
splice donor/acceptor (+/-2bp)		11 clinvar	5 clinvar			16
Total	19	21	167	66	3	276

Highest pathogenic variant AF is 0.0000805635

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 179 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001353108.3	RefSeq	NP_001340037.1	14	MANE Select
ENST00000675561.1	Ensembl	ENSP00000502085.1	14	MANE Select
NM_001042383.2	RefSeq	NP_001035842.1	11	Standard
NM_001042384.2	RefSeq	NP_001035843.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

ATM Signaling Network in Development and Disease
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

Biological Process

DNA damage checkpoint
G2/M transition of mitotic cell cycle
centriole replication
regulation of G2/M transition of mitotic cell cycle
signal transduction in response to DNA damage

Molecular Function

protein binding

Cellular Component

spindle pole
centrosome
centriole
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337090
Coding exons: 14
Length: 89275
Individuals with no LoFs: 125601
Homozygous LoFs: 0
Heterozygous LoFs: 147
Defined: 125748
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0983	366	361	1.01	0.0000180	4678
Missense (PolyPhen)		97	95.255	1.0183		1258
Synonymous	0.723	113	123	0.917	0.00000582	1223
Loss of Function	0.216	38	39.5	0.963	0.00000191	494

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00038	0.00038	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00076	0.00076	rare
South Asian	0.00079	0.00078	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for normal spindle assembly. Plays a key role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication. Reported to be required for centrosomal recruitment of CEP152; however, this function has been questioned (PubMed:21983783, PubMed:26297806). Also recruits CDK1 to centrosomes (PubMed:21406398). Plays a role in DNA damage response. Following DNA damage, such as double-strand breaks (DSBs), is removed from centrosomes; this leads to the inactivation of spindle assembly and delay in mitotic progression (PubMed:21406398). {ECO:0000269|PubMed:21406398, ECO:0000269|PubMed:21983783, ECO:0000269|PubMed:26297806}.;
Disease: DISEASE: Seckel syndrome 6 (SCKL6) [MIM:614728]: 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:21983783}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.108

Intolerance Scores

LoFtool: 1.00
RVIS EVS: -0.42
RVIS percentile EVS: 25.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.347

Gene Damage Prediction

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