RIMS2

protein-coding

regulating synaptic membrane exocytosis 2, the group of Regulating synaptic membrane exocytosis family|PDZ domain containing

Gene summary

The protein encoded by this gene is a presynaptic protein that interacts with RAB3, a protein important for normal neurotransmitter release. The encoded protein can also bind several other synaptic proteins, including UNC-13 homolog B, ELKS/Rab6-interacting/CAST family member 1, and synaptotagmin 1. This protein is involved in synaptic membrane exocytosis. Polymorphisms in this gene have been associated with degenerative lumbar scoliosis. [provided by RefSeq, Feb 2017]

Previous symbols:

RAB3IP3

MANE transcript

NM_001348484.3

Inheritance

ClinVar variants

P:7U:201B:23

Top phenotype

Cone-rod synaptic disorder syndrome, congenital nonprogressive

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr8:103,500,610-104,254,430

External References & Databases

Ensembl (ENSG00000176406)

Transcript & Mutation Effects

hg38 • Region Span ~753.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod synaptic disorder syndrome, congenital nonprogressiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033543

Submitter: PanelApp Australia

cone-rod synaptic disorder syndrome, congenital nonprogressiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033543

Submitter: Labcorp Genetics (formerly Invitae)

cone-rod synaptic disorder syndrome, congenital nonprogressiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0033543

Submitter: G2P

cone-rod synaptic disorder, congenital nonprogressiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012490

Submitter: Franklin by Genoox

Identification of Bi-allelic RIMS2 Variants in Seven Cases of CRSD from Four Unrelated Families. https://doi.org/10.1016/j.ajhg.2020.04.018

cone-rod synaptic disorder syndrome, congenital nonprogressiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033543

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cone-rod synaptic disorder syndrome, congenital nonprogressiveAR

Manifestation: Endocrine; Neurologic; Ophthalmologic

Intervention: Endocrine

Rationale: Among other features, metabolic dysfunction (including hyperglycemia and insulin resistance) has been described and suggested as an age-related manifestation, and awareness may allow early identification and management

Refs: 32470375

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIMS2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 199

not providedTotal: 34

Cone-rod synaptic disorder syndrome, congenital nonprogressiveTotal: 11

RIMS2-related disorderTotal: 3

Cone-rod synaptic disorder, congenital nonprogressiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001348484.3. 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			2 clinvar	11 clinvar	4 clinvar	17
missense			197 clinvar	6 clinvar	2 clinvar	205
nonsense	4 clinvar	1 clinvar				5
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	2 clinvar			4
Total	5	2	201	17	6	231

Highest pathogenic variant AF is 0.000032137068

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001348484.3	RefSeq	NP_001335413.1	30	MANE Select
ENST00000696799.1	Ensembl	ENSP00000512879.1	30	MANE Select
NM_001100117.3	RefSeq	NP_001093587.1	24	Standard
NM_001282881.2	RefSeq	NP_001269810.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Insulin secretion - Homo sapiens (human)

Biological Process

intracellular protein transport
positive regulation of gene expression
calcium ion regulated exocytosis
regulation of exocytosis
cAMP-mediated signaling

Molecular Function

protein binding
Rab GTPase binding
ion channel binding
metal ion binding

Cellular Component

cell junction
presynaptic membrane
synapse
presynaptic active zone
cytoskeleton of presynaptic active zone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000406091
Coding exons: 24
Length: 755347
Individuals with no LoFs: 124763
Homozygous LoFs: 0
Heterozygous LoFs: 32
Defined: 124795
p: 0.000128

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.776	697	757	0.921	0.0000422	8727
Missense (PolyPhen)		316	396.17	0.79763		4526
Synonymous	-0.559	269	258	1.04	0.0000131	2626
Loss of Function	7.38	10	82.2	0.122	0.00000520	888

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00071	0.00071	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.000057	0.000056	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0.00020	0.00020	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Rab effector involved in exocytosis. May act as scaffold protein. Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000269|PubMed:23999003}.;

Recessive Scores

pRec: 0.131

Intolerance Scores

LoFtool: 0.783
RVIS EVS: -0.59
RVIS percentile EVS: 18.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.592

Gene Damage Prediction

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