CCDC22

protein-coding

coiled-coil domain containing 22, the group of CCC complex

Gene summary

This gene encodes a protein containing a coiled-coil domain. The encoded protein functions in the regulation of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) by interacting with COMMD (copper metabolism Murr1 domain-containing) proteins. The mouse orthologous protein has been shown to bind copines, which are calcium-dependent, membrane-binding proteins that may function in calcium signaling. This human gene has been identified as a novel candidate gene for syndromic X-linked intellectual disability. [provided by RefSeq, Aug 2013]

Previous symbols:

CXorf37

MANE transcript

NM_014008.5

Inheritance

XL, AR

ClinVar variants

P:4U:184B:62

Top phenotype

Ritscher-Schinzel syndrome 2

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:49,235,470-49,250,520

External References & Databases

Ensembl (ENSG00000101997)

Transcript & Mutation Effects

hg38 • Region Span ~15.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Ritscher-Schinzel syndrome 2LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010499

Submitter: Ambry Genetics

Ritscher-Schinzel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019078

Submitter: Orphanet

Ritscher-Schinzel syndrome 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010499

Submitter: G2P

Ritscher-Schinzel syndrome 2STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010499

Submitter: Labcorp Genetics (formerly Invitae)

Ritscher-Schinzel syndrome 2LIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0010499

Submitter: Ambry Genetics

epilepsyLIMITED

Inheritance Pattern: XL

Disease ID:MONDO:0005027

Submitter: Ambry Genetics

Ritscher-Schinzel syndrome 2MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010499

Submitter: ClinGen

*CCDC22* was first reported as a cause of syndromic X-linked intellectual disability in 2012 (Voineagu et al., PMID: 21826058) in a large Australian family. A missense variant affecting splicing and leading to decreased mRNA expression was identified in six affected males. In 2022, Rodgers et al. (PMID: 36073196) provided detailed phenotypic information for eight affected males in this family. Common features included global developmental delay, intellectual disability, typical facies, congenital heart disease, posterior fossa malformations, short stature, ectodermal abnormalities, and genital and skeletal anomalies. The clinical presentation is consistent with Ritscher-Schinzel syndrome 2, also known as cranio-cerebro-cardiac (3C) syndrome. Since then, four additional variants (3 missense and 1 inframe deletion) have been reported in six individuals with similar features (PMIDs: 24916641, 33059814, 34020006, 36130690). Two of the missense variants were detected in families with two affected siblings each. Additional missense variants have been identified in large sequencing studies of individuals with intellectual disability or autism spectrum disorder (PMIDs: 19377476, 23563313, 25363768, 31906484); however, as clinical data of these individuals were not provided, these variants were not scored. *CCDC22* is not significantly constrained for missense variants (Z = 1.29; gnomAD v2.1.1), but is intolerant to truncating variants (pLI = 1.0, LOEUF = 0.123). The mechanism of pathogenicity is not fully understood, but there is some evidence of loss of function (PMID: 21826058, 23563313, 24916641). *CCDC22* encodes a protein known as coiled-coil domain containing 22, which is a component of the Commander complex that plays a role in endosomal recycling. This gene-disease relationship is supported by alterations in patient-derived cells (PMIDs: 21826058, 23563313, 24916641, 31537807) and CCDC22 interactions with cullin proteins (CUL3, CUL4B) previously implicated in intellectual disability and other neurodevelopmental disorders. In summary, there is moderate evidence to support the relationship between *CCDC22* and Ritscher-Schinzel syndrome 2. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 7, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Ritscher-Schinzel syndrome 2XL

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 21826058; 24916641

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CCDC22 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 122

not providedTotal: 106

Ritscher-Schinzel syndrome 2Total: 43

CCDC22-related disorderTotal: 15

Intellectual disabilityTotal: 7

Ritscher-Schinzel syndrome 1Total: 2

ObesityTotal: 1

Familial thoracic aortic aneurysm and aortic dissectionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014008.5. 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			7 clinvar	26 clinvar	1 clinvar	34
missense	2 clinvar	2 clinvar	161 clinvar	32 clinvar	3 clinvar	200
nonsense			3 clinvar			3
start loss			1 clinvar			1
frameshift						0
splice donor/acceptor (+/-2bp)			12 clinvar			12
Total	2	2	184	58	4	250

Highest pathogenic variant AF is 9.1157534e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 48 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014008.5	RefSeq	NP_054727.1	17	MANE Select
ENST00000376227.4	Ensembl	ENSP00000365401.3	17	MANE Select
ENST00000904953.1	Ensembl	ENSP00000575012.1	17	Standard
ENST00000904953.2	Ensembl	ENSP00000575012.1	17	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

cellular copper ion homeostasis
Golgi to plasma membrane transport
cytoplasmic sequestering of NF-kappaB
protein transport
positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

protein binding
cullin family protein binding

Cellular Component

cellular_component
nucleoplasm
endosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376227
Coding exons: 17
Length: 15061
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	1.29	211	271	0.779	0.0000244	3966
Missense (PolyPhen)		49	98.817	0.49587		1523
Synonymous	-0.0883	109	108	1.01	0.00000880	1337
Loss of Function	4.56	0	24.2	0.00	0.00000182	386

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: Involved in regulation of NF-kappa-B signaling. Promotes ubiquitination of I-kappa-B-kinase subunit IKBKB and its subsequent proteasomal degradation leading to NF-kappa-B activation; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex. May down-regulate NF- kappa-B activity via association with COMMD1 and involving a CUL2- dependent E3 ubiquitin ligase complex. Regulates the cellular localization of COMM domain-containing proteins, such as COMMD1 and COMMD10 (PubMed:23563313). Plays a role in copper ion homeostasis. Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes (PubMed:25355947). {ECO:0000269|PubMed:23563313, ECO:0000269|PubMed:25355947}.;

Recessive Scores

pRec: 0.150

Intolerance Scores

RVIS EVS: 0.71
RVIS percentile EVS: 85.68

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.307

Gene Damage Prediction

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