RIPOR2

protein-coding

RHO family interacting cell polarization regulator 2, the group of Armadillo like helical domain containing

Gene summary

This gene encodes an atypical inhibitor of the small G protein RhoA. Inhibition of RhoA activity by the encoded protein mediates myoblast fusion and polarization of T cells and neutrophils. The encoded protein is a component of hair cell stereocilia that is essential for hearing. A splice site mutation in this gene results in hearing loss in human patients. [provided by RefSeq, Sep 2016]

Previous symbols:

C6orf32
FAM65B

MANE transcript

NM_001286445.3

Inheritance

AD, AR

ClinVar variants

P:2U:238B:98

Top phenotype

Deafness, autosomal dominant 21; Deafness, autosomal recessive 104

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr6:24,804,282-25,042,170

External References & Databases

Ensembl (ENSG00000111913)

Transcript & Mutation Effects

hg38 • Region Span ~237.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 21MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0011761

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 104MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014675

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 104LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014675

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing lossLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: ClinGen

RIPOR2 was first reported in relation to autosomal dominant nonsyndromic genetic deafness in 2020 (de Brujin et al; PMID: 32631815). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive nonsyndromic genetic deafness (OMIM:616515) and autosomal dominant nonsyndromic genetic deafness (OMIM:607017). The split curation for autosomal recessive nonsyndromic genetic deafness has been curated separately. One variant (in-frame deletion) that has been reported in over fifty probands from twelve families (with a founder effect demonstrated for at least seven of the families) in one publication (PMIDs: 32631815) is included in this curation. Analysis of this variant in mice shows mislocalization, supporting impaired function of protein. Thus, the mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level evidence, PMID: 24958875). Heterozygous mutant mice show mild hearing loss. Expression-level evidence indicates that the gene is expressed in inner and outer hair cells. 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 classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 5/15/2024 (SOP Version 10).

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 104LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014675

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing loss 21LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0011761

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

RIPOR2 was first reported in relation to autosomal recessive nonsyndromic genetic deafness in 2014 (Diaz-Horta et al.; PMID: 24958875). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two disease entities, autosomal recessive nonsyndromic genetic deafness (OMIM:616515) and autosomal dominant nonsyndromic genetic deafness (OMIM:607017). The split curation for autosomal dominant nonsyndromic genetic deafness has been curated separately. Two variants (splice-site, nonsense) that have been reported in nine probands in two publications (PMIDs: 24958875, 37864412) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, zebrafish model, expression-level evidence, functional alteration evidence; PMIDs: 24958875, 27269051, 30280293). Mutant mice and zebrafish show significant hearing loss. Expression-level evidence indicates that the gene is expressed in inner and outer hair cells. The gene is shown to interact with MYH9, which is classified as definitive for an autosomal dominant condition, of which hearing loss is a feature. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 9/18/2018. It was re-evaluated on 5/15/2024. As a result of this reevaluation, the classification changed from moderate to strong, due to the addition of genetic evidence and experimental evidence (protein interaction evidence) (PMIDs: 30280293, 37864412). In summary, there is strong evidence to support the relationship between RIPOR2 and autosomal recessive nonsyndromic hearing loss. More than two publications of genetic evidence are required for a definitive classification, and there are currently only two. We will re-evaluate this gene-disease relationship in the future to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Hearing Loss GCEP on the meeting date 5/15/2024 (SOP Version 10).

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 21; Deafness, autosomal recessive 104AD/AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Comments: The age of onset of hearing loss in Deafness, autosomal dominant 21 has been described as highly variable

Refs: 24958875; 32631815

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIPOR2 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 363

not specifiedTotal: 192

RIPOR2-related disorderTotal: 73

Autosomal recessive nonsyndromic hearing loss 104Total: 5

Autosomal dominant nonsyndromic hearing loss 21Total: 5

Nonsyndromic genetic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001286445.3. 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			4 clinvar	66 clinvar	3 clinvar	73
missense			224 clinvar	21 clinvar	8 clinvar	253
nonsense		1 clinvar	6 clinvar			7
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	1	1	238	87	11	338

Highest pathogenic variant AF is 0.0000024785666

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001286445.3	RefSeq	NP_001273374.1	22	MANE Select
ENST00000643898.2	Ensembl	ENSP00000494268.2	22	MANE Select
NM_001286446.3	RefSeq	NP_001273375.1	14	Standard
NM_001286447.2	RefSeq	NP_001273376.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ripor2	Danio rerio	Structure: muscle Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

ripor2

Danio rerio

Structure: muscle

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

chemotaxis
cell adhesion
negative regulation of cell adhesion
sensory perception of sound
negative regulation of Rho protein signal transduction

Molecular Function

protein binding
identical protein binding
14-3-3 protein binding

Cellular Component

cytoplasm
cytoskeleton
apical plasma membrane
filopodium
stereocilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259698
Coding exons: 22
Length: 244638
Individuals with no LoFs: 124611
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 124619
p: 0.0000321

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.37	400	557	0.718	0.0000292	6954
Missense (PolyPhen)		150	205.95	0.72834		2690
Synonymous	1.86	192	228	0.843	0.0000130	2099
Loss of Function	5.21	9	47.9	0.188	0.00000242	624

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0.000089	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.0000089	0.0000089	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization (PubMed:17150207, PubMed:24687993, PubMed:23241886, PubMed:24958875, PubMed:25588844, PubMed:27556504). Inhibits chemokine-induced T lymphocyte responses, such as cell adhesion, polarization and migration (PubMed:23241886). Involved also in the regulation of neutrophil polarization, chemotaxis and adhesion (By similarity). Required for normal development of inner and outer hair cell stereocilia within the cochlea of the inner ear (By similarity). Plays a role for maintaining the structural organization of the basal domain of stereocilia (By similarity). Involved in mechanosensory hair cell function (By similarity). Required for normal hearing (PubMed:24958875). {ECO:0000250|UniProtKB:Q80U16, ECO:0000269|PubMed:17150207, ECO:0000269|PubMed:23241886, ECO:0000269|PubMed:24687993, ECO:0000269|PubMed:24958875, ECO:0000269|PubMed:27556504}.;
Disease: DISEASE: Deafness, autosomal recessive, 104 (DFNB104) [MIM:616515]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:24958875}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0981

Intolerance Scores

RVIS EVS: 2.4
RVIS percentile EVS: 98.52

Essentials

Essential (gene trap): N