# NM_003921.5(BCL10):c.207dup (p.Asp70fs)

https://sugi.bio/variant/bcl10-p-asp70fs

## Summary

**BCL10 p.Asp70fs (c.207dup)** is classified **Pathogenic** in BCL10 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-25). Associated with immunodeficiency 37.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the BCL10 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to immunodeficiency 37.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024994/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BCL10](https://sugi.bio/atlas/gene/BCL10/) |
| Protein change (HGVS p.) | p.Asp70fs |
| Coding change (HGVS c.) | c.207dup |
| MANE Select transcript | [NM_003921](https://www.ncbi.nlm.nih.gov/nuccore/NM_003921) |
| Variant type | Duplication |
| Location | chr1:85270756-85270757 (GRCh38) |
| ClinVar | [VCV3651130](https://www.ncbi.nlm.nih.gov/clinvar/variation/3651130/) |

**All HGVS expressions:** `LRG_1210:g.11148dup`, `LRG_1210t1:c.207dup`, `NC_000001.10:g.85736440dup`, `NC_000001.11:g.85270757dup`, `NG_012216.2:g.11148dup`, `NM_001320715.2:c.207dup`, `NM_003921.5:c.207dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.655, GERP 2.08, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.637, pLI 0.73351. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**BCL10** population constraint: LOEUF 0.637, pLI 0.73351, missense-Z 1.844. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **immunodeficiency 37** — Definitive (AR)

## Protein context {#protein}

Residue **70** lies in the card domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 70.43, 37% of residues very-high.

**5 experimental structure(s)** (PDB): [2MB9](https://www.rcsb.org/structure/2MB9), [6BZE](https://www.rcsb.org/structure/6BZE), [6GK2](https://www.rcsb.org/structure/6GK2), [8CZD](https://www.rcsb.org/structure/8CZD), [8CZO](https://www.rcsb.org/structure/8CZO).

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

*Describes the biological roles of BCL10 (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:** BCL10's established molecular role includes protease binding. p.Asp70fs falls in the card domain.


### Pathways affected {#pathways}

BCL10 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [E3 ubiquitin ligases ubiquitinate target proteins](https://reactome.org/content/detail/R-HSA-8866654) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | electronic |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | electronic |

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

**Molecular function:** protease binding, transcription coactivator activity, protein-macromolecule adaptor activity, ubiquitin protein ligase binding, identical protein binding, protein kinase B binding.

**Biological process:** toll-like receptor signaling pathway, adaptive immune response, negative regulation of mature B cell apoptotic process, programmed cell death, positive regulation of protein ubiquitination, lipopolysaccharide-mediated signaling pathway.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-25.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-04-25 |

## Associated conditions {#conditions}

[immunodeficiency 37](https://sugi.bio/atlas/disease/immunodeficiency-37/).

**Reported phenotype names (ClinVar):** Immunodeficiency 37.

## Similar variants {#similar}

Related BCL10 variant pages (same residue, condition, or type): [BCL10 p.Pro6fs](/variant/bcl10-p-pro6fs), [BCL10 p.Ser121dup](/variant/bcl10-p-ser121dup), [BCL10 c.346+8dup](/variant/bcl10-c-346-plus-8dup), [BCL10 c.58-3dup](/variant/bcl10-c-58-minus-3dup), [BCL10 p.Arg232Ter](/variant/bcl10-p-arg232ter), [BCL10 p.Arg87Gln](/variant/bcl10-p-arg87gln), [BCL10 p.Cys119Tyr](/variant/bcl10-p-cys119tyr), [BCL10 p.Gln97Glu](/variant/bcl10-p-gln97glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3651130). 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.*