ODAD2

protein-coding

outer dynein arm docking complex subunit 2, the group of Outer dynein arm docking complex subunits|Armadillo repeat containing

Gene summary

The protein encoded by this gene contains ten Armadillo repeat motifs (ARMs) and one HEAT repeat, and is thought to be involved in ciliary and flagellar movement. This protein has been shown to localize to the ciliary axonemes and at the ciliary base of respiratory cells. Studies indicate that mutations in this gene cause partial outer dynein arm (ODA) defects in respiratory cilia. The cilia of cells with mutations in this gene displayed either reduced ciliary beat frequency and amplitude, or, complete immotility. Some individuals with primary ciliary dyskensia (PCD) have been shown to have mutations in this gene. PCD is characterized by chronic airway disease and left/right body asymmetry defects. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Previous symbols:

ARMC4

MANE transcript

NM_018076.5

Inheritance

AD, AR

ClinVar variants

P:63U:316B:199

Top phenotype

Ciliary dyskinesia, primary, 23

gnomAD constraint

pLI —, LoF o/e 0.89

Max pathogenic AF

—

Genomic locus

chr10:27,775,186-27,999,079

External References & Databases

Ensembl (ENSG00000169126)

Transcript & Mutation Effects

hg38 • Region Span ~223.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary ciliary dyskinesiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

primary ciliary dyskinesia 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014193

Submitter: G2P

primary ciliary dyskinesia 23DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014193

Submitter: ClinGen

*ODAD2* (*ARMC4*) was first reported in relation to autosomal recessive primary ciliary dyskinesia 23 (PCD23) with or without situs inversus in 2013 (Hjeij et al., PMID: 23849778). PCD23 is one of 50 primary ciliary dyskinesias that have been observed to be inherited in a monogenic fashion. Most PCD patients present with a chronic productive cough, recurrent respiratory infection, and chronic rhinosinusitis. Some patients also demonstrate situs inversus and neonatal respiratory distress (PMID:23849778). 8 variants (1 missense, 5 nonsense, 1 frameshift, and 1 large deletion) that have been reported in 8 probands across 2 publications (PMIDs: 2389778, 24203976) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. High-speed video microscopy of the respiratory cilia in 4 probands with *ODAD2* mutations showed reduced or absent ciliary beating. Transmission electron microscopy of these cilia showed a reduction or lack of outer dynein arms, which suggests that the *ODAD2* protein is important for the assembly of the outer dynein arm structure (PMIDs: 23849778, 24203976). This gene-disease relationship is also supported by biochemical evidence, expression data, model systems, and rescue experiments (PMIDs: 24055424, 27486780, 23715323, 23849778). First, *ODAD1* is also involved in the outer dyenin arm docking complex and is definitively associated with PCD20, which supports *ODAD2* also having a role in PCD (PMID: 27486780). Secondly, GTEx expression data shows high levels of *ODAD2* expression in the lungs, testes, and fallopian tubes, which is consistent with the PCD phenotype (PMID: 27486780). Next, fruit fly and zebrafish model systems demonstrate the respective PCD phenotypes of infertility and situs inversus (PMIDs: 24055424, 23849778). Finally, the situs inversus phenotype in the zebrafish was significantly rescued using a human copy of *ODAD2* (PMID:23849778). In summary, *ODAD2* is definitively associated with autosomal recessive primary ciliary dyskinesia 23. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on the meeting date 11/10/2022 (SOP Version 9).

primary ciliary dyskinesia 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014193

Submitter: Labcorp Genetics (formerly Invitae)

primary ciliary dyskinesia 23STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014193

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Ciliary dyskinesia, primary, 23AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Pulmonary

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Pulmonary

Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary; Individuals may require surgery or other interventions related to congenital cardiac malformations

Refs: 23849778; 24203976

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ODAD2 variants in ClinVar

8 Conditions Cataloged

Primary ciliary dyskinesia 23Total: 496

Primary ciliary dyskinesiaTotal: 330

not providedTotal: 92

ODAD2-related disorderTotal: 23

not specifiedTotal: 5

Male infertilityTotal: 2

Kartagener syndromeTotal: 1

Fetal anomalies with a likely genetic causeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018076.5. 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			3 clinvar	162 clinvar	3 clinvar	168
missense		2 clinvar	310 clinvar	32 clinvar	2 clinvar	346
nonsense	16 clinvar	2 clinvar	1 clinvar			19
start loss						0
frameshift	23 clinvar	3 clinvar	1 clinvar			27
splice donor/acceptor (+/-2bp)	1 clinvar	16 clinvar	1 clinvar			18
Total	40	23	316	194	5	578

Highest pathogenic variant AF is 0.00012925071

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 58 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018076.5	RefSeq	NP_060546.2	19	MANE Select
ENST00000305242.10	Ensembl	ENSP00000306410.5	19	MANE Select
NM_001290020.2	RefSeq	NP_001276949.1	19	Standard
NM_001290021.2	RefSeq	NP_001276950.1	11	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
armc4	Danio rerio	Structure: heart looping Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

armc4

Danio rerio

Structure: heart looping

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cilium movement
regulation of cilium beat frequency
determination of left/right symmetry
heart development
ventricular system development

Cellular Component

axoneme
ciliary base

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000305242
Coding exons: 19
Length: 223863
Individuals with no LoFs: 125610
Homozygous LoFs: 0
Heterozygous LoFs: 138
Defined: 125748
p: 0.000549

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.511	526	560	0.939	0.0000304	6793
Missense (PolyPhen)		174	199.31	0.87299		2388
Synonymous	0.389	194	201	0.965	0.0000109	2005
Loss of Function	0.700	41	46.1	0.889	0.00000210	657

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00039	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00066	0.00065	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00067	0.00067	rare
South Asian	0.00047	0.00046	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ciliary protein that may be involved in a late step of axonemal outer dynein arm assembly. {ECO:0000269|PubMed:23849778}.;

Recessive Scores

pRec: 0.0909

Intolerance Scores

LoFtool: 0.380
RVIS EVS: 1.12
RVIS percentile EVS: 92.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.131

Gene Damage Prediction

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