CCDC50

protein-coding

coiled-coil domain containing 50

Gene summary

This gene encodes a soluble, cytoplasmic, tyrosine-phosphorylated protein with multiple ubiquitin-interacting domains. Mutations in this gene cause nonsyndromic, postlingual, progressive sensorineural DFNA44 hearing loss. In mouse, the protein is expressed in the inner ear during development and postnatal maturation and associates with microtubule-based structures. This protein may also function as a negative regulator of NF-kB signaling and as an effector of epidermal growth factor (EGF)-mediated cell signaling. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

Previous symbols:

C3orf6
DFNA44

MANE transcript

NM_178335.3

Inheritance

ClinVar variants

P:2U:154B:59

Top phenotype

Deafness, autosomal dominant 44

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr3:191,329,085-191,398,659

External References & Databases

Ensembl (ENSG00000152492)

Transcript & Mutation Effects

hg38 • Region Span ~69.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

*CCDC50* was first reported in relation to autosomal dominant nonsyndromic hearing loss in 2007 (Modamio-Hoybjor et al., PMID:17503326). Four variants (missense, frameshift) that have been reported in 4 probands in 4 publications (PMIDs: 17503326, 34416374, 33229591, 37165931) are included in this curation. Variants in this gene segregated with disease in 14 additional family members (PMID:17503326). The mechanism of pathogenicity is unknown. This gene-disease association is also supported by an expression study (PMID:17503326). A knockdown mouse model showed no difference in auditory brainstem response thresholds between mutants and controls, so it was not scored (PMID: 37165931). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on 12/15/2017 as per SOP v6. It was reevaluated on 6/25/2024 using SOP v10. As a result of this reevaluation, this record underwent an update in scoring to be consistent with SOP v10. New case level and functional evidence has been reviewed or added, but the classification did not change (PMIDs: 34416374, 33229591, 37165931).

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 44LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011832

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing loss 44LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0011832

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 44AD

Manifestation: Audiologic/Otolaryngologic

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

Comments: Hearing loss has been reported to occur in the first decade (6-10 years)

Refs: 12483295; 17503326

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCDC50 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 194

not specifiedTotal: 109

CCDC50-related disorderTotal: 28

Autosomal dominant nonsyndromic hearing loss 44Total: 10

Nonsyndromic genetic hearing lossTotal: 2

Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_178335.3. 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			1 clinvar	32 clinvar		33
missense			143 clinvar	24 clinvar	3 clinvar	170
nonsense		1 clinvar	4 clinvar			5
start loss						0
frameshift	1 clinvar		4 clinvar			5
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	1	154	56	3	215

Highest pathogenic variant AF is 6.841995e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_178335.3	RefSeq	NP_848018.1	12	MANE Select
ENST00000392455.9	Ensembl	ENSP00000376249.4	12	MANE Select
NM_174908.4	RefSeq	NP_777568.1	11	Standard
ENST00000392456.4	Ensembl	ENSP00000376250.4	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGFR1

Biological Process

sensory perception of sound

Molecular Function

protein binding
ubiquitin protein ligase binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000392456
Coding exons: 12
Length: 69594
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125747
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0720	258	261	0.987	0.0000142	3164
Missense (PolyPhen)		73	87.352	0.8357		1067
Synonymous	-0.174	95	92.9	1.02	0.00000493	847
Loss of Function	2.70	16	32.7	0.490	0.00000192	359

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in EGFR signaling. {ECO:0000269|PubMed:15314609}.;
Disease: DISEASE: Deafness, autosomal dominant, 44 (DFNA44) [MIM:607453]: A form of non-syndromic deafness characterized by initially moderate hearing loss that affects mainly low to mid frequencies. Later, it progresses to involve all the frequencies and leads to a profound hearing loss by the 6th decade. {ECO:0000269|PubMed:17503326}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0930

Intolerance Scores

LoFtool: 0.937
RVIS EVS: 1.26
RVIS percentile EVS: 93.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.433

Gene Damage Prediction

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