c.2536_2539dup
FrameshiftF2PathogenicLumenal · 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 847 marked. Right: the same model with the non-native (scrambled) and lost region (residues 847–890) marked — what the frameshift transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 847 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
- Lumenal loop 4554–573
- Transmembrane helix 9574–594
- Cytoplasmic loop 5 / pre-lumenal595–599
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in South Asian: AF 0.0023% (2 of 86,246 alleles), 16.9x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| South Asian | 0.0023% | 2 / 86,246 | 0 | ~1 in 21560 |
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.2536_2539dup — WFS1 Molecular Atlas Card
Variant type: Frameshift Frameshift point: residue 847 Predicted premature stop (PTC): residue 847 Domain context (where the frame breaks): C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
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 847
- Predicted PTC: aa 847 (0 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 847 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 – 846 (95.1% of full-length protein)
- Non-native scrambled stretch: aa 847 – 846 (0 residues of out-of-frame sequence)
- Lost beyond the PTC: aa 847 – 890 (44 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 600–846 retained; aa 847–890 replaced by non-native sequence
Native domains downstream of the frameshift (lost or non-native)
(no full native domains downstream)
Clinical evidence
Inheritance and scope
Pathogenic — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
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.
- Classification: Pathogenic
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.2536_2539dup
- ClinVar accession: VCV002702063
- Last evaluated: 2023/12/10 00:00
- Submissions: 1
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 2026-06-08T02:16:38.928506Z.
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.