TRIM2

protein-coding

tripartite motif containing 2, the group of Tripartite motif family|Ring finger proteins

Gene summary

The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic filaments. It plays a neuroprotective role and functions as an E3-ubiquitin ligase in proteasome-mediated degradation of target proteins. Mutations in this gene can cause early-onset axonal neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

MANE transcript

NM_015271.5

Inheritance

ClinVar variants

P:6U:265B:173

Top phenotype

Charcot-Marie-Tooth disease, axonal, type 2R

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr4:153,152,163-153,339,319

External References & Databases

Ensembl (ENSG00000109654)

Transcript & Mutation Effects

hg38 • Region Span ~187.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 2RLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014208

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 2RLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014208

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 2RSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014208

Submitter: Orphanet

Charcot-Marie-Tooth disease type 2RSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014208

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, axonal, type 2RAR

Manifestation: 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: 23562820; 25893792

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRIM2 variants in ClinVar

5 Conditions Cataloged

Charcot-Marie-Tooth disease type 2RTotal: 462

not specifiedTotal: 79

not providedTotal: 69

TRIM2-related disorderTotal: 9

Peripheral axonal neuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015271.5. 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			4 clinvar	169 clinvar	2 clinvar	175
missense	1 clinvar	1 clinvar	247 clinvar	2 clinvar		251
nonsense		1 clinvar	4 clinvar			5
start loss						0
frameshift	2 clinvar	1 clinvar	7 clinvar			10
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	3	3	265	171	2	444

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 171 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015271.5	RefSeq	NP_056086.2	12	MANE Select
ENST00000338700.10	Ensembl	ENSP00000339659.5	12	MANE Select
NM_001130067.2	RefSeq	NP_001123539.1	11	Standard
NM_001302692.2	RefSeq	NP_001289621.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
trim2a	Danio rerio	Structure: myeloid cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

trim2a

Danio rerio

Structure: myeloid cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cytokine Signaling in Immune system
Immune System
Interferon gamma signaling
Interferon Signaling

Biological Process

protein polyubiquitination
proteasome-mediated ubiquitin-dependent protein catabolic process
regulation of neuron apoptotic process

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding
ubiquitin protein ligase activity

Cellular Component

cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000338700
Coding exons: 12
Length: 186979
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125748
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.57	248	465	0.534	0.0000277	5092
Missense (PolyPhen)		58	156.07	0.37162		1720
Synonymous	1.19	176	197	0.892	0.0000138	1515
Loss of Function	4.76	4	34.0	0.118	0.00000194	372

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000039	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11. Plays a neuroprotective function. May play a role in neuronal rapid ischemic tolerance. {ECO:0000250|UniProtKB:Q9ESN6}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 2R (CMT2R) [MIM:615490]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. {ECO:0000269|PubMed:23562820}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.266
RVIS EVS: -1.11
RVIS percentile EVS: 6.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.738

Gene Damage Prediction

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