RTN2

Chr 19ARAD

reticulon 2

Also known as: HMNR11, NSP2, NSPL1, NSPLI, SPG12

NCBI Gene: 6253 ENSG00000125744 UniProt: O75298 OMIM: 603183

The RTN2 protein localizes to the endoplasmic reticulum where it inhibits amyloid precursor protein processing and enhances trafficking of transporters including glutamate and glucose transporters to the cell surface. Mutations cause either autosomal dominant spastic paraplegia-12 or autosomal recessive distal hereditary motor neuronopathy with spasticity, both affecting motor neurons and causing progressive spasticity. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.417), and the differing inheritance patterns suggest distinct pathogenic mechanisms for different mutation types.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene belongs to the family of reticulon encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. Reticulon proteins also play an important role in the replication of positive-strand RNA (ssRNA) viruses. Mutations at this locus have been associated with autosomal dominant spastic paraplegia-12. [provided by RefSeq, Aug 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.422 OMIM phenotypes

Clinical Summary— RTN2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 179 VUS of 356 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — RTN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.416

Z-score 4.05

OE 0.22 (0.13–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.70Z-score

OE missense 0.89 (0.81–0.98)

306 obs / 342.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.13–0.42)

0≤0.351.4

Missense OE?0.89 (0.81–0.98)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 7 / 31.5Missense obs/exp: 306 / 342.5Syn Z: 0.72

This gene — mechanism propensity

0.5770th %ile

GOF

0.7029th %ile

LOF

0.4430th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 94% of P/LP variants are LoF · LOEUF 0.42

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFPatient 11 has a heterozygous frameshift variant in RTN2. As two of the three SPG12-causing variants in this gene described to date are null variants, haploinsufficiency of RTN2 seems to cause SPG12.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27165006 ↗

ClinVar Variant Classifications

356 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic8

VUS179

Likely Benign106

Benign28

Conflicting22

Pathogenic

Likely Pathogenic

179

VUS

106

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	0	1	0	8
Likely Pathogenic	8	0	0	0	8
VUS	6	158	11	4	179
Likely Benign	0	17	29	60	106
Benign	0	0	20	8	28
Conflicting	—				22
Total	21	175	61	72	351

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap RTN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →