# c.2080_2105del — WFS1 Molecular Atlas Card

**Variant type:** Frameshift
**Frameshift point:** residue 694
**Predicted premature stop (PTC):** residue 702
**Domain context (where the frame breaks):** C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

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## Schema category: **F2 — Frameshift, NMD-escape — scrambled C-terminus produced**

The premature stop falls in the last exon (exon 8), so NMD does not degrade the transcript and a protein IS produced — native sequence up to the frameshift point, then a non-native (scrambled) stretch to the new stop. The garbled C-terminus may misfold or mis-insert and can interfere with folding/membrane insertion of the upstream domains. Behavior is highly variable and typically too compromised for chaperone rescue; gene therapy is the primary path. Wet-lab validation recommended.

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## Premature-stop prediction

- **Frameshift point:** aa 694
- **Predicted PTC:** aa 702 (8 codons downstream of the frame break)
- **Method:** deterministic translation of edited NM_006005.3 CDS (frameshift position = first changed residue, HGVS convention)
- **Confidence:** high

## NMD prediction

- **Status:** NMD-escape
- **Confidence:** high
- **Reasoning:** Stop codon at position 702 is in the last exon (exon 8, starts ~aa 413). NMD does not target stop codons in the last exon — a truncated protein is produced.

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## Protein consequence

- **Native (wild-type) sequence retained:** aa 1 – 693 (77.9% of full-length protein)
- **Non-native scrambled stretch:** aa 694 – 701 (8 residues of out-of-frame sequence)
- **Lost beyond the PTC:** aa 702 – 890 (189 residues)

### Native domains retained (upstream of the frameshift)
- N-terminal cytoplasmic (intrinsically disordered) (aa 1–310)
- Transmembrane helix 1 (aa 311–331)
- Cytoplasmic loop 1 (aa 332–340)
- Transmembrane helix 2 (aa 341–361)
- Lumenal loop 1 (aa 362–370)
- Transmembrane helix 3 (aa 371–391)
- Cytoplasmic loop 2 (aa 392–400)
- Transmembrane helix 4 (aa 401–421)
- Lumenal loop 2 (aa 422–431)
- Transmembrane helix 5 (aa 432–452)
- Cytoplasmic loop 3 (aa 453–461)
- Transmembrane helix 6 (aa 462–482)
- Lumenal loop 3 (aa 483–496)
- Transmembrane helix 7 (aa 497–517)
- Cytoplasmic loop 4 (aa 518–532)
- Transmembrane helix 8 (aa 533–553)
- Lumenal loop 4 (aa 554–573)
- Transmembrane helix 9 (aa 574–594)
- Cytoplasmic loop 5 / pre-lumenal (aa 595–599)

### Domain interrupted at the frameshift point
- **C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)** — native aa 600–693 retained; aa 694–890 replaced by non-native sequence

### Native domains downstream of the frameshift (lost or non-native)
_(no full native domains downstream)_

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## Clinical evidence

- **Classification:** Pathogenic
- **Review status:** criteria provided, single submitter
- **cDNA change:** c.2080_2105del
- **ClinVar accession:** VCV002892325
- **Last evaluated:** 2023/10/05 00:00
- **Submissions:** 1

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## Why this variant matters

Because the frame breaks late, in the last exon, the transcript escapes NMD and a protein is actually made: wild-type wolframin up to the break, then a stretch of non-native sequence to a new stop. That scrambled C-terminus is the wildcard — it can drag the upstream domains out of fold. The atlas quantifies exactly how much native protein survives and how long the non-native tail is — the data a wet-lab needs to predict behavior.

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_Card generated by `wolfram-atlas-batch` skill (v2 — frameshift pipeline) on 2026-06-08T02:16:15.612592Z._
_NMD rule and schema definitions: `reference/nmd_rules.md`, `reference/card_schema_extension.md`._
_CDS reference: NM_006005.3 (171..2843). WFS1 reference: UniProt O76024, AlphaFold model v6._