c.1705_1706del
FrameshiftF2Pathogenic/Likely pathogenicTransmembrane · predictedF2 — Frameshift, NMD-escape — scrambled C-terminus produced
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 569 marked. Right: the same model with the non-native (scrambled) and lost region (residues 569–890) marked — what the frameshift transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 604 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.
Therapeutic Implication · F2
Protein Domains
- N-terminal cytoplasmic (intrinsically disordered)1–310
- Transmembrane helix 1311–331
- Cytoplasmic loop 1332–340
- Transmembrane helix 2341–361
- Lumenal loop 1362–370
- Transmembrane helix 3371–391
- Cytoplasmic loop 2392–400
- Transmembrane helix 4401–421
- Lumenal loop 2422–431
- Transmembrane helix 5432–452
- Cytoplasmic loop 3453–461
- Transmembrane helix 6462–482
- Lumenal loop 3483–496
- Transmembrane helix 7497–517
- Cytoplasmic loop 4518–532
- Transmembrane helix 8533–553
- Transmembrane helix 9574–594
- Cytoplasmic loop 5 / pre-lumenal595–599
- C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)600–890
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic/Likely pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: no ClinVar review status recorded. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Feed this card to Wolfram Intelligence
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Full Variant Card
c.1705_1706del — WFS1 Molecular Atlas Card
Variant type: Frameshift Frameshift point: residue 569 Predicted premature stop (PTC): residue 604 Domain context (where the frame breaks): Lumenal loop 4
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.
Premature-stop prediction
- Frameshift point: aa 569
- Predicted PTC: aa 604 (35 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 604 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.
Protein consequence
- Native (wild-type) sequence retained: aa 1 – 568 (63.8% of full-length protein)
- Non-native scrambled stretch: aa 569 – 603 (35 residues of out-of-frame sequence)
- Lost beyond the PTC: aa 604 – 890 (287 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)
Domain interrupted at the frameshift point
- Lumenal loop 4 — native aa 554–568 retained; aa 569–573 replaced by non-native sequence
Native domains downstream of the frameshift (lost or non-native)
- Transmembrane helix 9 (aa 574–594)
- Cytoplasmic loop 5 / pre-lumenal (aa 595–599)
- C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (aa 600–890)
Clinical evidence
Inheritance and scope
Pathogenic/Likely pathogenic — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Pathogenic/Likely pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Not found in the cached WFS1 ClinVar set (_reference/WFS1_clinvar_variants.csv).
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.
Card generated by wolfram-atlas-batch skill (v2 — frameshift pipeline) on 2026-06-08T02:15:50.458138Z.
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.