c.1027_1028del

FrameshiftF2Pathogenic/Likely pathogenicTransmembrane · predicted

Frameshift variant · frameshift point at position 343 · Transmembrane helix 2 · WFS1 (Wolframin)

F2 — Frameshift, NMD-escape — scrambled C-terminus produced

Wild-type vs Translated Product

Wild-type · full length

Full wild-type wolframin · 890 aa — frameshift point at residue 343

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Translated product

Native sequence to residue 342; 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 343 marked. Right: the same model with the non-native (scrambled) and lost region (residues 343–890) marked — what the frameshift transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type

Frameshift

NMD status

NMD-escape

high confidence

Schema

Frameshift, NMD-escape — scrambled C-terminus produced

Native protein retained

38.4%

PTC at aa 541

Stop codon at position 541 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

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.

Protein Domains

Retained (aa 1–342)

N-terminal cytoplasmic (intrinsically disordered)1–310
Transmembrane helix 1311–331
Cytoplasmic loop 1332–340

Lost / non-native (downstream)

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.1027_1028del

ClinVar variantc.1027_1028del

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.1027_1028del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this F2 frameshift variant and its domain context.

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Full Variant Card

c.1027_1028del — WFS1 Molecular Atlas Card

Variant type: Frameshift Frameshift point: residue 343 Predicted premature stop (PTC): residue 541 Domain context (where the frame breaks): Transmembrane helix 2

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

Premature-stop prediction

Frameshift point: aa 343
Predicted PTC: aa 541 (198 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 541 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 – 342 (38.4% of full-length protein)
Non-native scrambled stretch: aa 343 – 540 (198 residues of out-of-frame sequence)
Lost beyond the PTC: aa 541 – 890 (350 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)

Domain interrupted at the frameshift point

Transmembrane helix 2 — native aa 341–342 retained; aa 343–361 replaced by non-native sequence

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

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

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 2026-06-08T02:14:58.496289Z. 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.