CCDC8

protein-coding

coiled-coil domain containing 8, the group of Protein phosphatase 1 regulatory subunits

Gene summary

This gene encodes a coiled-coil domain-containing protein. The encoded protein functions as a cofactor required for p53-mediated apoptosis following DNA damage, and may also play a role in growth through interactions with the cytoskeletal adaptor protein obscurin-like 1. Mutations in this gene are a cause of 3M syndrome-3 (3M3). [provided by RefSeq, Dec 2011]

MANE transcript

NM_032040.5

Inheritance

AD, AR

ClinVar variants

P:19U:159B:68

Top phenotype

Three M syndrome 3

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr19:46,410,329-46,413,564

External References & Databases

Ensembl (ENSG00000169515)

Transcript & Mutation Effects

hg38 • Region Span ~3.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 40LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014475

Submitter: Illumina

3-M syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007477

Submitter: Orphanet

3M syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013627

Submitter: G2P

3M syndrome 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013627

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Three M syndrome 3AR

Manifestation: Craniofacial; Musculoskeletal

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: 21737058

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCDC8 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 151

Inborn genetic diseasesTotal: 95

not specifiedTotal: 47

3M syndrome 3Total: 25

CCDC8-related disorderTotal: 8

Monogenic short statueTotal: 3

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

ImmunodeficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032040.5. 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			2 clinvar	46 clinvar	3 clinvar	51
missense			145 clinvar	18 clinvar	1 clinvar	164
nonsense		4 clinvar	3 clinvar			7
start loss		1 clinvar	1 clinvar			2
frameshift	1 clinvar	13 clinvar	8 clinvar			22
splice donor/acceptor (+/-2bp)						0
Total	1	18	159	64	4	246

Highest pathogenic variant AF is 0.000013643022

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032040.5	RefSeq	NP_114429.2	1	MANE Select
ENST00000307522.5	Ensembl	ENSP00000303158.3	1	MANE Select
ENST00000697726.1	Ensembl	ENSP00000513420.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Neddylation

Biological Process

microtubule cytoskeleton organization
regulation of mitotic nuclear division
negative regulation of phosphatase activity
post-translational protein modification

Molecular Function

protein binding

Cellular Component

nucleus
cytoplasm
centrosome
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307522
Coding exons: 1
Length: 3213
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.159	319	311	1.03	0.0000172	3455
Missense (PolyPhen)		85	94.144	0.90288		1061
Synonymous	-1.24	144	126	1.14	0.00000687	1129
Loss of Function	1.88	2	7.58	0.264	3.34e-7	82

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Core component of the 3M complex, a complex required to regulate microtubule dynamics and genome integrity. It is unclear how the 3M complex regulates microtubules, it could act by controlling the level of a microtubule stabilizer (PubMed:24793695, PubMed:24793696). Required for localization of CUL7 to the centrosome (PubMed:24793695). {ECO:0000269|PubMed:24793695, ECO:0000269|PubMed:24793696}.;
Disease: DISEASE: 3M syndrome 3 (3M3) [MIM:614205]: A disorder characterized by poor postnatal growth and distinctive facial features, including triangular facies, frontal bossing, fleshy tipped nose, and fleshy lips. Other features may include skeletal anomalies and prominent heels. {ECO:0000269|PubMed:21737058, ECO:0000269|PubMed:23018678}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0683

Intolerance Scores

LoFtool: 0.674
RVIS EVS: 1.44
RVIS percentile EVS: 95.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.112

Gene Damage Prediction

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