CCDC88C

protein-coding

coiled-coil domain containing 88C

Gene summary

This gene encodes a ubiquitously expressed coiled-coil domain-containing protein that interacts with the dishevelled protein and is a negative regulator of the Wnt signalling pathway. The protein encoded by this gene has a PDZ-domain binding motif in its C-terminus with which it interacts with the dishevelled protein. Dishevelled is a scaffold protein involved in the regulation of the Wnt signaling pathway. The Wnt signaling pathway plays an important role in embryonic development, tissue maintenance, and cancer progression. Mutations in this gene cause autosomal recessive, primary non-syndromic congenital hydrocephalus; a condition characterized by excessive accumulation of cerebrospinal fluid in the ventricles of the brain. [provided by RefSeq, Jan 2013]

Previous symbols:

KIAA1509

MANE transcript

NM_001080414.4

Inheritance

AD, AR

ClinVar variants

P:120U:513B:786

Top phenotype

Spinocerebellar ataxia 40; Hydrocephalus, congenital, 1

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr14:91,271,323-91,417,844

External References & Databases

Ensembl (ENSG00000015133)

Transcript & Mutation Effects

hg38 • Region Span ~146.5 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: Ambry Genetics

spinocerebellar ataxia type 40SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014475

Submitter: Orphanet

hydrocephalus, nonsyndromic, autosomal recessive 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009360

Submitter: Genomics England PanelApp

hydrocephalus, nonsyndromic, autosomal recessive 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009360

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 40LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014475

Submitter: Labcorp Genetics (formerly Invitae)

hydrocephalus, nonsyndromic, autosomal recessive 1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009360

Submitter: Ambry Genetics

spinocerebellar ataxia type 40MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014475

Submitter: Genomics England PanelApp

hydrocephalus, nonsyndromic, autosomal recessive 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009360

Submitter: G2P

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 40; Hydrocephalus, congenital, 1AD/AR

Manifestation: 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: 21031079; 23042809; 25062847

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCDC88C variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1434

Inborn genetic diseasesTotal: 384

not specifiedTotal: 116

Hydrocephalus, nonsyndromic, autosomal recessive 1Total: 91

Spinocerebellar ataxia type 40Total: 71

CCDC88C-related disorderTotal: 67

Intellectual disabilityTotal: 5

HydrocephalusTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080414.4. 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	662 clinvar	24 clinvar	689
missense		3 clinvar	505 clinvar	85 clinvar	15 clinvar	608
nonsense	27 clinvar	10 clinvar	2 clinvar			39
start loss						0
frameshift	35 clinvar	20 clinvar	2 clinvar			57
splice donor/acceptor (+/-2bp)	1 clinvar	24 clinvar	1 clinvar			26
Total	63	57	513	747	39	1419

Highest pathogenic variant AF is 0.00001058018

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080414.4	RefSeq	NP_001073883.2	30	MANE Select
ENST00000389857.11	Ensembl	ENSP00000374507.6	30	MANE Select
ENST00000389856.9	Ensembl	ENSP00000374506.5	4	Standard
ENST00000553403.1	Ensembl	ENSP00000451392.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ectoderm Differentiation
Signaling by WNT
Signal Transduction
Negative regulation of TCF-dependent signaling by DVL-interacting proteins
TCF dependent signaling in response to WNT

Biological Process

regulation of protein phosphorylation
Wnt signaling pathway
cytoskeleton-dependent intracellular transport
stress-activated protein kinase signaling cascade
cytoplasmic microtubule organization

Molecular Function

microtubule binding
PDZ domain binding
protein self-association
dynein light intermediate chain binding

Cellular Component

cytoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389857
Coding exons: 30
Length: 146522
Individuals with no LoFs: 124702
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 124768
p: 0.000265

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.708	1104	1.17e+3	0.942	0.0000759	13061
Missense (PolyPhen)		350	392.88	0.89086		4753
Synonymous	-0.725	552	531	1.04	0.0000369	4022
Loss of Function	5.91	31	92.2	0.336	0.00000480	1064

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00046	0.00045	rare
Latino/Admixed American	0.00044	0.00038	rare
Ashkenazi Jewish	0.00070	0.00070	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00025	0.00023	rare
South Asian	0.00017	0.00016	rare
Other	0.00052	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negative regulator of the canonical Wnt signaling pathway, acting downstream of DVL to inhibit CTNNB1/Beta-catenin stabilization (By similarity). May also activate the JNK signaling pathway (PubMed:25062847). {ECO:0000250|UniProtKB:Q6VGS5, ECO:0000269|PubMed:25062847}.;
Disease: DISEASE: Hydrocephalus, congenital, 1 (HYC1) [MIM:236600]: A form of congenital hydrocephalus, a disease characterized by onset in utero of enlarged ventricles due to accumulation of ventricular cerebrospinal fluid. Affected individuals may have neurologic impairment. HYC1 inheritance is autosomal recessive. {ECO:0000269|PubMed:21031079, ECO:0000269|PubMed:23042809}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia 40 (SCA40) [MIM:616053]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA40 is an autosomal dominant, slowly progressive form. Brain MRI shows pontocerebellar atrophy along with a global reduction in brain volume. {ECO:0000269|PubMed:25062847}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.504
RVIS EVS: 1.14
RVIS percentile EVS: 92.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.135

Gene Damage Prediction

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