Rare disease genomics
COL6A1 deep-intronic variant in suspected muscular dystrophy
Read the task instructions and deliverables
# Vanilla Claude Code Controlled Packet Run: construction_9d1b952a_20260910_real_bam You are the `vanilla_claude_code` system arm for a controlled benchmark packet. Work only from this sandbox. Do not read paths outside this sandbox, and do not look for or read lynnvironment skills, benchmark truth, answer keys, scorecards, generation manifests, raw BAM/CRAM/FASTQ files, or genotype files outside `case/input/`. Approved VCF/VCF.GZ files are model-visible benchmark inputs when present in `case/input/`. Use all search, literature, and database tools available in this runtime when they can strengthen the interpretation. External services may receive only small identifiers such as gene symbols, disease names, HPO terms, rsIDs, or narrow variant coordinates. Do not upload packet files or raw genomic content to external search, literature, or database services. Do not search for this benchmark case id, benchmark truth, answer keys, or prior benchmark outputs. There is no numeric cap on external search/database calls. Keep research evidence-driven and within an approximately US$10 total per-case inference and paid-tool budget: do not repeat a request without a changed question or input, and do not use a paid service unless it could resolve a material evidence gap. Prioritize direct ClinVar/gnomAD records, primary literature, and authoritative gene-disease sources. Stop external research once the leading candidates have adequate evidence for the report or the available evidence ceiling is clear. Log every external request as one JSON object per line in `external_queries.jsonl`, including the tool or service, exact query/parameters, purpose, returned stable identifiers or URLs, and whether it changed the assessment. Create the log even if no external request is needed. Read these sandbox files first: 1. `schema/final_report.schema.json` 2. `case/input/phenotype.txt` 3. `case/input/genotype_summary.md` if present; otherwise inspect the approved genotype files in `case/input/`, such as `.vcf`, `.vcf.gz`, and index files Task: Produce one machine-readable diagnosis artifact from the visible packet only. Output requirements: - Return only one raw JSON object as your final answer. No Markdown and no prose. - If your agent runtime writes files, write the same object to `final_report.json` in the sandbox root. - Use `schema`: exactly `lynnvironment.final_report.v1`. - Use `case_id`: `construction_9d1b952a_20260910_real_bam`. - Use `system_id`: `vanilla_claude_code`. - Use `model`: `claude-fable-5-1` if known, otherwise `unknown`. - Use `genome_build`: `GRCh38`. - Include `candidates` and `case_diagnosis`. - If reporting a candidate, preserve `chrom`, `pos`, `ref`, and `alt` exactly from visible caller rows under `variant`. - If a visible caller row provides a mechanism/class label such as `single_nucleotide_variant` or `small_indel`, preserve that exact observed caller label as candidate `variant_class`. - Use candidate `event_structure` for event geometry such as `single_nucleotide_variant`, `small_indel`, `cnv_deletion`, `bnd`, `balanced_translocation`, or `inversion`. - Use candidate `functional_effect` for clinical/functional effect if you can support one from the visible packet; otherwise use `unknown` and explain the limitation. - Do not collapse structure and biology into one label; for example, a regulatory BND can have `event_structure: balanced_translocation` and `functional_effect: noncoding_regulatory`. - Use only variants present in the genotype packet caller rows. - Use phenotype free text and HPO terms from the phenotype packet when assessing phenotype fit, but do not treat synthetic phenotype context as clinical validation or as a reason to overclaim pathogenicity. - Use the visible packet as the sole source of case-specific genotype and phenotype facts. Use external search and database tools for current gene-disease, population, clinical, functional, and literature evidence. - Do not invent citations, PMIDs, ClinVar/gnomAD assertions, allele frequencies, segregation, validation, ACMG criteria, coordinates, alleles, or classifications. - Each evidence entry must cite the visible packet or a searched external source. For external evidence, include a stable identifier or direct URL and the precise supported claim. Clearly label unsourced recollection as unsupported model background knowledge. - If evidence is insufficient for a confident classification, use `uncertain_significance` or report no candidate rather than overclaiming. - Include explicit limitations: research decision support, not clinical sign-out; no orthogonal validation unless visible in the packet; no BAM-level discovery or variant calling unless explicitly provided in the packet workflow; state whether the genotype review was compact-summary, bounded-VCF, or full-VCF based on the visible inputs. - Do not include benchmark-internal truth, answer keys, generation metadata, event lists, or grading fields in the output. For `case_diagnosis.status`, use: - `diagnostic` only when the packet supports a confident molecular diagnosis; - `candidate_finding` when a plausible candidate is surfaced but limitations prevent diagnosis-grade certainty; - `no_finding` when no packet-supported candidate explains the phenotype.
How was it graded?
Single LLM judge scoring weighted rubric dimensions against truth.json; separate pass/fail verdict.
Weighted average of applicable rubric scores, each from 0 to 1, rounded to six decimals. Dimensions marked not applicable are excluded from the average.
LLM judge: gpt-5.6-sol
Task files
Choose an evidence file.
Grading criteria
Causal finding
Earns credit
Recognize the complete required causal finding in COL6A1, including every required allele or event member. Required GRCh38 DNA changes: chr21:45989967 C>T. A single member of a multi-member event is incomplete. Optional findings do not invalidate a complete answer. Top-K recall requires all required findings in the first K causal ranks without unrelated findings interleaved; top-3 recall requires all by rank 3. For a multi-member event, use the worst member rank unless it is correctly grouped as one event.
Weight: 0.2
Recorded result / fable 5 1
The sole required causal event is absent; the report instead concludes no_finding.
Variant identification
Earns credit
Identify all required DNA changes on GRCh38: chr21:45989967 C>T. These are the reference sequence representations; evaluate equivalent representations using the original judge rules. Naming the gene alone is not sufficient. Missing an allele or a required member makes the variant identification incomplete; gene recognition is scored separately.
Weight: 0.15
Recorded result / fable 5 1
The exact causal deep-intronic SNV is missing; the same-gene rank-2 variant is biologically different.
Gene identification
Earns credit
Identify the causal gene: COL6A1. This dimension scores gene identity separately from the exact variant: identifying the correct gene can earn gene credit even when the reported allele is wrong. It does not by itself satisfy the causal-finding or variant-identification checks.
Weight: 0.1
Recorded result / fable 5 1
COL6A1 is recognized as a relevant collagen VI disease gene at rank 2, but the report associates it only with a different benign allele and rejects causality.
Event completeness
Earns credit
Judge zygosity, phase, inheritance, event grouping, gene mechanism, and functional consequence. Penalize an unphased recessive pair presented as proven trans, a heterozygous-only recessive assertion, a coding-only account when a regulatory allele is required, or a digenic truth reduced to one gene. Partial event recognition deserves partial—not zero—credit unless it produces a confidently wrong diagnosis.
Weight: 0.1
Recorded result / fable 5 1
The report does not capture the causal variant's constitutional heterozygosity, de novo dominant inheritance, or splice-altering mechanism.
Classification
Earns credit
Use the reference classification policy for each required finding: chr21:45989967 C>T: pathogenic or likely pathogenic. Respect the case confidence ceiling: diagnostic. A classification within one ACMG tier can receive partial credit but cannot override an explicit candidate-only ceiling.
Weight: 0.1
Recorded result / fable 5 1
No pathogenic or likely pathogenic classification is assigned to the required variant; the only COL6A1 candidate is a different likely-benign allele.
Case disposition
Earns credit
The case conclusion must capture the complete required finding at the supported confidence, with no fatal alternate diagnosis or material overclaim. The reference case-status ceiling is diagnostic. Finding the correct gene alone is not a complete diagnosis. Case success is assessed separately from the weighted rubric score.
Weight: 0.1
Recorded result / fable 5 1
The report's no_finding disposition contradicts the truth's diagnostic ceiling and required diagnostic causal event.
Overclaim and restraint
Earns credit
Penalize classification overclaim, causal-scope overclaim, unsupported alternate diagnoses, and diagnostic use of a known decoy. Do not penalize a clearly labeled incidental or noncausal finding merely for being listed. Reward explicit rejection of a decoy for the correct biological reason. Set `negative_false_positive` true whenever a hard-negative report makes a confident diagnosis or pathogenic causal assertion.
Weight: 0.1
Recorded result / fable 5 1
The report is appropriately restrained about its listed VUSs, but overstates search completeness by calling the review full-VCF and concluding no small-variant finding while admitting deep-intronic variants were not annotated.
Artifact contract
Earns credit
The report must be valid JSON with the expected report identity, a usable case diagnosis, and a ranked candidate list. Wrong case ID, wrong reference build, duplicate/invalid ranks, internally contradictory top-level disposition, or a report that cannot be interpreted is a contract failure. Minor extra fields or harmless representation differences are not failures.
Weight: 0.05
Recorded result / fable 5 1
The report is valid JSON with the correct case ID and GRCh38 build, a usable diagnosis, and unique consecutive candidate ranks 1–4.
Evidence and reasoning
Earns credit
Evaluate whether report evidence actually supports identity, pathogenicity, mechanism, and case relevance. Multiple independent, traceable sources are stronger than repeated assertions from one source. Missing provenance, vague evidence, or evidence that supports the gene but not the exact variant reduces credit. Do not demand literature beyond what is necessary to compare with truth.
Weight: 0.05
Recorded result / fable 5 1
The report provides traceable evidence for rejecting its listed candidates, but none supports the identity, pathogenicity, inheritance, or mechanism of the true causal variant.
Decoy handling
Earns credit
Penalize classification overclaim, causal-scope overclaim, unsupported alternate diagnoses, and diagnostic use of a known decoy. Do not penalize a clearly labeled incidental or noncausal finding merely for being listed. Reward explicit rejection of a decoy for the correct biological reason. Set `negative_false_positive` true whenever a hard-negative report makes a confident diagnosis or pathogenic causal assertion.
Weight: 0.05
Recorded result / fable 5 1
The authoritative truth specifies no planted decoys.