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c.2141_2164del

In-frame indelI3Uncertain significanceLumenal · predicted
In-frame indel variant · indel site at position 714 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

I3 — Multi-residue in-frame indel — likely major structural disruption

Wild-type vs Modified Structure

Wild-type · full length
Wild-type wolframin · 890 aa — AlphaFold reference
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Modified product
Modified product · c.2141_2164del — Cα-RMSD 5.13 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 8-aa in-frame deletion product — the affected region near residue 714 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.13 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I3
Multi-residue in-frame indel — likely major structural disruption
Domain
C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Backbone Cα-RMSD
5.13 Å
vs WT · folded core (n=482)

Modified-sequence structure resolved. The 8-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.1) and superposed on the wild-type AlphaFold model. Kabsch-superposed Cα-RMSD over high-confidence (WT pLDDT>70) residues N-terminal to the lesion; cross-pipeline, includes ~few-Å method baseline

Therapeutic Implication · I3

8 residues removed in frame around position 714 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)). A change this size usually perturbs local packing and can propagate to the fold. Gene therapy is the primary path unless an AlphaFold prediction of the modified sequence shows a surprisingly intact fold. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationUncertain significance
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.00020%
cDNA changec.2141_2164del
ClinVar variantNM_006005.3(WFS1):c.2141_2164del (p.Asn714_Asn721del)
ClinVar accessionVCV002671775
Last evaluated2023/02/14 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.2141_2164del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I3 in-frame indel variant and its domain context.

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Full Variant Card

c.2141_2164del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 8 residue(s) deleted in frame at position 714 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption

8 residues removed in frame around position 714 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)). A change this size usually perturbs local packing and can propagate to the fold. Gene therapy is the primary path unless an AlphaFold prediction of the modified sequence shows a surprisingly intact fold. Predicted structure pending (ColabFold).

Structural prediction

  • Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
  • Affected domain: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
  • Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

  • Classification: Uncertain significance
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.2141_2164del
  • ClinVar accession: VCV002671775
  • Last evaluated: 2023/02/14 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:38.964201Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.