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c.683_684del

FrameshiftF1Pathogenic/Likely pathogenicCytoplasmic · predicted
Frameshift variant · frameshift point at position 228 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

F1 — Frameshift, NMD-targeted — null allele

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — frameshift point at residue 228
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Translated product
Native sequence to residue 227; everything highlighted is non-native (scrambled) or lost
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Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 228 marked. Right: the same model with the non-native (scrambled) and lost region (residues 228–890) marked — what the frameshift transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Frameshift
NMD status
NMD-targeted
high confidence
Schema
F1
Frameshift, NMD-targeted — null allele
Native protein retained
25.5%
PTC at aa 245

Stop codon at position 245 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.

Therapeutic Implication · F1

The frameshift creates a premature termination codon well upstream of the last exon-exon junction; the 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No frameshifted protein is produced — functionally a null allele. Therapeutic options: (a) translational readthrough drugs (Ataluren/PTC124, aminoglycosides) — notably LESS effective for frameshifts than for nonsense variants, because reading through the PTC still yields out-of-frame protein; (b) gene therapy via allele replacement is the higher-yield path.

Protein Domains

Retained (aa 1–227)
—
Lost / non-native (downstream)
  • 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
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)600–890

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic
Review status—
Associated conditions—
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.683_684del
ClinVar variantc.683_684del
ClinVar accession—
Last evaluated—

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.683_684del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this F1 frameshift variant and its domain context.

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Full Variant Card

c.683_684del — WFS1 Molecular Atlas Card

Variant type: Frameshift Frameshift point: residue 228 Predicted premature stop (PTC): residue 245 Domain context (where the frame breaks): N-terminal cytoplasmic (intrinsically disordered)

Schema category: F1 — Frameshift, NMD-targeted — null allele

The frameshift creates a premature termination codon well upstream of the last exon-exon junction; the 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No frameshifted protein is produced — functionally a null allele. Therapeutic options: (a) translational readthrough drugs (Ataluren/PTC124, aminoglycosides) — notably LESS effective for frameshifts than for nonsense variants, because reading through the PTC still yields out-of-frame protein; (b) gene therapy via allele replacement is the higher-yield path.

Premature-stop prediction

  • Frameshift point: aa 228
  • Predicted PTC: aa 245 (17 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-targeted
  • Confidence: high
  • Reasoning: Stop codon at position 245 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.

Protein consequence

  • Native (wild-type) sequence retained: aa 1 – 227 (25.5% of full-length protein)
  • Non-native scrambled stretch: aa 228 – 244 (17 residues of out-of-frame sequence)
  • Lost beyond the PTC: aa 245 – 890 (646 residues)

Native domains retained (upstream of the frameshift)

(no domains fully retained)

Domain interrupted at the frameshift point

  • N-terminal cytoplasmic (intrinsically disordered) — native aa 1–227 retained; aa 228–310 replaced by non-native sequence

Native domains downstream of the frameshift (lost or non-native)

  • 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)
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (aa 600–890)

Clinical evidence

Not found in the cached WFS1 ClinVar set (_reference/WFS1_clinvar_variants.csv).

Why this variant matters

The frame breaks early enough that the premature stop is caught by nonsense-mediated decay — the transcript is degraded before any out-of-frame protein accumulates. That makes this, in effect, a clean null allele: the atlas points the therapeutic conversation at gene replacement, and notes that readthrough drugs are a weaker fit here than for true nonsense variants because reading through the stop still yields scrambled protein.

Card generated by wolfram-atlas-batch skill (v2 — frameshift pipeline) on 2026-06-08T02:17:06.094710Z. 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.