# NM_005619.5(RTN2):c.271_289del (p.Arg91fs)

https://sugi.bio/variant/rtn2-p-arg91fs

## Summary

**RTN2 p.Arg91fs (c.271_289del)** is classified **Uncertain significance** in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-23).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter

## For patients & families {#patients}

This is a change in the RTN2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RTN2](https://sugi.bio/atlas/gene/RTN2/) |
| Protein change (HGVS p.) | p.Arg91fs |
| Coding change (HGVS c.) | c.271_289del |
| MANE Select transcript | [NM_005619](https://www.ncbi.nlm.nih.gov/nuccore/NM_005619) |
| Variant type | Deletion |
| Location | chr19:45494796-45494814 (GRCh38) |
| ClinVar | [VCV4687046](https://www.ncbi.nlm.nih.gov/clinvar/variation/4687046/) |

**All HGVS expressions:** `NC_000019.10:g.45494797_45494815del`, `NC_000019.9:g.45998055_45998073del`, `NG_032157.1:g.7240_7258del`, `NM_005619.5:c.271_289del`, `NM_206900.3:c.271_289del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 4.842, GERP 1.82, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.748, pLI 4.9773e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RTN2** population constraint: LOEUF 0.748, pLI 4.9773e-06, missense-Z 0.74227. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **91** lies in a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 50.99, 0% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-23.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-23 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related RTN2 variant pages (same residue, condition, or type): [RTN2 p.Arg91His](/variant/rtn2-p-arg91his), [RTN2 p.Gly309fs](/variant/rtn2-p-gly309fs), [RTN2 p.Gly57fs](/variant/rtn2-p-gly57fs), [RTN2 c.1381-12del](/variant/rtn2-c-1381-minus-12del), [RTN2 p.Leu385fs](/variant/rtn2-p-leu385fs), [RTN2 c.818_828del](/variant/rtn2-c-818-828del), [RTN2 p.Asp408fs](/variant/rtn2-p-asp408fs), [RTN2 p.Glu158fs](/variant/rtn2-p-glu158fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4687046). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*