# NM_170662.5(CBLB):c.2689+2del

https://sugi.bio/variant/cblb-c-2689-plus-2del

## Summary

**CBLB c.2689+2del** is classified **Likely pathogenic** in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-30). Very rare (popmax 0.0022%, sas); Associated with autoimmune disease, multisystem, infantile-onset, 3.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the CBLB gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to autoimmune disease, multisystem, infantile-onset, 3.

*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 | [CBLB](https://sugi.bio/atlas/gene/CBLB/) |
| Coding change (HGVS c.) | c.2689+2del |
| MANE Select transcript | [NM_170662](https://www.ncbi.nlm.nih.gov/nuccore/NM_170662) |
| Variant type | Deletion |
| Location | chr3:105670231-105670231 (GRCh38) |
| ClinVar | [VCV4849425](https://www.ncbi.nlm.nih.gov/clinvar/variation/4849425/) |

**All HGVS expressions:** `LRG_1179:g.204322del`, `LRG_1179t1:c.2689+2del`, `NC_000003.11:g.105389075del`, `NC_000003.12:g.105670231del`, `NG_055547.1:g.204322del`, `NM_001321786.1:c.2773+2del`, `NM_001321788.2:c.2689+2del`, `NM_001321789.1:c.2626+2del`, `NM_001321790.2:c.2623+2del`, `NM_001321791.2:c.2557+2del`, `NM_001321793.2:c.2557+2del`, `NM_001321794.2:c.2542+2del`, `NM_001321795.2:c.2542+2del`, `NM_001321796.2:c.2542+2del`, `NM_001321797.2:c.2410+2del`, `NM_001321798.2:c.2410+2del`, `NM_001321799.2:c.2410+2del`, `NM_001321806.2:c.1909+2del`, `NM_001321807.2:c.1909+2del`, `NM_001321808.2:c.1777+2del`, `NM_001321811.2:c.1762+2del`, `NM_001321813.1:c.1762+2del`, `NM_001321816.2:c.1630+2del`, `NM_001321820.2:c.1369+2del`, `NM_001321822.2:c.1360+2del`, `NM_170662.5:c.2689+2del`, `NM_170662.5:c.2689+2delT`

## 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 0.601, GERP 2.01, phastCons 0.998 — weakly conserved position
- Molecular consequence: **canonical splice-site (±1/±2)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.406, pLI 0.99998), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Splice region: **canonical splice dinucleotide (donor +2)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 0.72**, o/e 0.94 (1 kb window 105,670,000–105,671,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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 (gnomAD v4.1): grpmax **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/91,054 in the highest group · 3/1,460,710 alleles overall — very rare (popmax 0.0022%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0022% | 45,527 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,462 |

*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}

**CBLB** population constraint: LOEUF 0.406, pLI 0.99998, missense-Z 1.8747. *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 62.88, 30% of residues very-high.

**36 experimental structure(s)** (PDB): [10YS](https://www.rcsb.org/structure/10YS), [10ZJ](https://www.rcsb.org/structure/10ZJ), [26LM](https://www.rcsb.org/structure/26LM), [2AK5](https://www.rcsb.org/structure/2AK5), [2BZ8](https://www.rcsb.org/structure/2BZ8), [2DO6](https://www.rcsb.org/structure/2DO6).

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

*Describes the biological roles of CBLB (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:** CBLB's established molecular role includes ubiquitin protein ligase activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Antigen processing: Ubiquitination & Proteasome degradation](https://reactome.org/content/detail/R-HSA-983168) | curated |

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

**Molecular function:** ubiquitin protein ligase activity.

**Biological process:** protein stabilization, negative regulation of T cell receptor signaling pathway, negative regulation of T cell activation, protein K63-linked ubiquitination.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-30.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| First Genomix Gene Laboratory, Genetic Diagnostics Department | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-05-30 |

## Associated conditions {#conditions}

[autoimmune disease, multisystem, infantile-onset, 3](https://sugi.bio/atlas/disease/autoimmune-disease-multisystem-infantile-onset-3/).

**Reported phenotype names (ClinVar):** Autoimmune disease, multisystem, infantile-onset, 3, CBLB DEFICIENCY.

## Similar variants {#similar}

Related CBLB variant pages (same residue, condition, or type): [CBLB c.2569+1609A>C](/variant/cblb-c-2569-plus-1609a-c), [CBLB p.Arg468Ter](/variant/cblb-p-arg468ter), [CBLB p.Cys436Trp](/variant/cblb-p-cys436trp), [CBLB p.His257Leu](/variant/cblb-p-his257leu), [CBLB c.2569+1del](/variant/cblb-c-2569-plus-1del), [CBLB c.1594-18del](/variant/cblb-c-1594-minus-18del), [CBLB c.1594-20_1594-18del](/variant/cblb-c-1594-minus-20-1594-minus-18del), [CBLB c.1594-21_1594-18del](/variant/cblb-c-1594-minus-21-1594-minus-18del).

### 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 4849425). 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.*