# NM_031938.7(BCO2):c.748_755del (p.Lys250fs)

https://sugi.bio/variant/bco2-p-lys250fs

## Summary

**BCO2 p.Lys250fs (c.748_755del)** is classified **Uncertain significance** in BCO2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-02-08). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: No assertion criteria · rsID rs2496488673 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BCO2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCO2](https://sugi.bio/atlas/gene/BCO2/) |
| Protein change (HGVS p.) | p.Lys250fs |
| Coding change (HGVS c.) | c.748_755del |
| MANE Select transcript | [NM_031938](https://www.ncbi.nlm.nih.gov/nuccore/NM_031938) |
| dbSNP | [rs2496488673](https://www.ncbi.nlm.nih.gov/snp/rs2496488673/) |
| Variant type | Deletion |
| Location | chr11:112199707-112199714 (GRCh38) |
| ClinVar | [VCV2497720](https://www.ncbi.nlm.nih.gov/clinvar/variation/2497720/) |

**All HGVS expressions:** `NC_000011.10:g.112199710_112199717del`, `NC_000011.9:g.112070433_112070440del`, `NM_001037290.4:c.646_653del`, `NM_001256397.3:c.646_653del`, `NM_001256398.3:c.529_536del`, `NM_001256400.3:c.433_440del`, `NM_031938.7:c.748_755del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.681, GERP -2.9, phastCons 0.99 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.047, pLI 8.0386e-13. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 12**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**BCO2** population constraint: LOEUF 1.047, pLI 8.0386e-13, missense-Z 0.59178. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.41, 78% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of BCO2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BCO2's established molecular role includes oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen.


### Pathways affected {#pathways}

BCO2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen.

**Biological process:** carotene metabolic process, carotene catabolic process.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2023-02-08.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo | Uncertain significance | no assertion criteria provided | research | 2023-02-08 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2497720). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*