RIN2

protein-coding

Ras and Rab interactor 2, the group of VPS9 domain containing

Gene summary

The RAB5 protein is a small GTPase involved in membrane trafficking in the early endocytic pathway. The protein encoded by this gene binds the GTP-bound form of the RAB5 protein preferentially over the GDP-bound form, and functions as a guanine nucleotide exchange factor for RAB5. The encoded protein is found primarily as a tetramer in the cytoplasm and does not bind other members of the RAB family. Mutations in this gene cause macrocephaly alopecia cutis laxa and scoliosis (MACS) syndrome, an elastic tissue disorder, as well as the related connective tissue disorder, RIN2 syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2011]

MANE transcript

NM_018993.4

Inheritance

ClinVar variants

P:20U:308B:205

Top phenotype

Macrocephaly, alopecia, cutis laxa, and scoliosis (MACS syndrome)

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr20:19,757,606-20,002,457

External References & Databases

Ensembl (ENSG00000132669)

Transcript & Mutation Effects

hg38 • Region Span ~244.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RIN2 syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: Orphanet

RIN2 syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: PanelApp Australia

RIN2 syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: ClinGen

RIN2 was first reported in relation to RIN2 syndrome (formerly MACS syndrome), an autosomal recessive lysosomal disease, in 2009 (Basel-Vanagaite L, et al.; PMID: 19631308). RIN2 encodes RAS and RAB interactor 2 and biallelic mutations in this gene are reported to cause cell trafficking dysfunction. Individuals with RIN2 syndrome have varying clinical features including macrocephaly, coarsening of facial features, down-slanting palpebral fissures, full everted lips, soft redundant skin, gum hypertrophy, irregular dentition, sparse scalp hair, joint hypermobility, and scoliosis. Four frameshift variants that have been reported in four probands in four publications (PMIDs: 19631308, 20424861, 24449201, 30769224) are included in this curation. In all cases, the variants presented in homozygosity. 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. This gene-disease relationship is also supported by expression studies that show this gene is expressed in fibroblasts, a relevant tissue, and studies showing that the expression level of the gene was markedly decreased when analyzed by qRT-PCR and absent when analyzed by immunoblotting (PMID: 19631308). In summary, there is definitive evidence supporting the relationship between RIN2 and autosomal recessive RIN2 syndrome. 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 Lysosomal Diseases GCEP on December 4, 2023 (SOP Version 9).

RIN2 syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: G2P

RIN2 syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: Labcorp Genetics (formerly Invitae)

RIN2 syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013115

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Macrocephaly, alopecia, cutis laxa, and scoliosis (MACS syndrome)AR

Manifestation: Craniofacial; Dental; Dermatologic; Musculoskeletal; 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: 19631308; 20424861; 21431621; 23963297;24449201

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIN2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 534

Inborn genetic diseasesTotal: 163

not specifiedTotal: 59

RIN2-related disorderTotal: 49

RIN2 syndromeTotal: 26

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018993.4. 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			6 clinvar	175 clinvar	4 clinvar	185
missense			288 clinvar	20 clinvar	6 clinvar	314
nonsense	3 clinvar	1 clinvar	3 clinvar			7
start loss						0
frameshift	9 clinvar	3 clinvar	6 clinvar			18
splice donor/acceptor (+/-2bp)		4 clinvar	5 clinvar			9
Total	12	8	308	195	10	533

Highest pathogenic variant AF is 0.0001482356

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018993.4	RefSeq	NP_061866.1	11	MANE Select
ENST00000255006.12	Ensembl	ENSP00000255006.7	11	MANE Select
NM_001242581.2	RefSeq	NP_001229510.1	12	Standard
NM_001378238.1	RefSeq	NP_001365167.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Rab regulation of trafficking
Posttranslational regulation of adherens junction stability and dissassembly
RAB GEFs exchange GTP for GDP on RABs

Biological Process

endocytosis
small GTPase mediated signal transduction
positive regulation of GTPase activity

Molecular Function

GTPase activator activity
Rab guanyl-nucleotide exchange factor activity
GTPase regulator activity

Cellular Component

cellular_component
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000255006
Coding exons: 12
Length: 115937
Individuals with no LoFs: 124622
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 124640
p: 0.0000722

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.724	490	537	0.912	0.0000309	6122
Missense (PolyPhen)		145	196.94	0.73628		2313
Synonymous	0.365	223	230	0.969	0.0000147	1864
Loss of Function	3.65	12	35.4	0.339	0.00000179	442

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000056	0.000056	rare
Finnish	0.000097	0.000093	rare
European (Non-Finnish)	0.000064	0.000062	rare
South Asian	0.00014	0.00013	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ras effector protein. May function as an upstream activator and/or downstream effector for RAB5B in endocytic pathway. May function as a guanine nucleotide exchange (GEF) of RAB5B, required for activating the RAB5 proteins by exchanging bound GDP for free GTP. {ECO:0000269|PubMed:11733506}.;

Recessive Scores

pRec: 0.133

Intolerance Scores

LoFtool: 0.602
RVIS EVS: 0.52
RVIS percentile EVS: 80.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.584

Gene Damage Prediction

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