TRIM2

Chr 4AR

tripartite motif containing 2

Also known as: CMT2R, RNF86

NCBI Gene: 23321 ENSG00000109654 UniProt: Q9C040 OMIM: 614141

The TRIM2 protein is an E3 ubiquitin ligase that mediates proteasome-mediated degradation of target proteins and plays a neuroprotective role in neurons. Mutations cause Charcot-Marie-Tooth disease type 2R, an early-onset axonal neuropathy, with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.27), indicating that heterozygous loss-of-function variants are likely not tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

ARLOEUF 0.271 OMIM phenotype

Clinical Summary— TRIM2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 272 VUS of 561 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.27LOEUF

pLI 0.996

Z-score 4.76

OE 0.12 (0.06–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.57Z-score

OE missense 0.53 (0.48–0.59)

248 obs / 464.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.27)

0≤0.351.4

Missense OE?0.53 (0.48–0.59)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 4 / 34.0Missense obs/exp: 248 / 464.6Syn Z: 1.19

ClinVar Variant Classifications

561 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS272

Likely Benign246

Benign24

Conflicting5

Pathogenic

Likely Pathogenic

272

VUS

246

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	1	0	0	3
Likely Pathogenic	2	1	0	0	3
VUS	14	246	10	2	272
Likely Benign	0	7	73	166	246
Benign	0	0	19	5	24
Conflicting	—				5
Total	18	255	102	173	553

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

28 pathogenic / likely-pathogenic (of 33) ClinVar copy-number / structural variants overlap TRIM2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →