# NM_002485.5(NBN):c.2108T>G (p.Ile703Ser)

https://sugi.bio/variant/nbn-p-ile703ser

## Summary

**NBN p.Ile703Ser (c.2108T>G)** is classified **Uncertain significance** in NBN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-03). AlphaMissense: likely pathogenic (0.9273); Absent from gnomAD v4.1; Associated with Nijmegen breakage syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1554555819 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the NBN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Nijmegen breakage syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003904/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NBN](https://sugi.bio/atlas/gene/NBN/) |
| Protein change (HGVS p.) | p.Ile703Ser |
| Coding change (HGVS c.) | c.2108T>G |
| MANE Select transcript | [NM_002485](https://www.ncbi.nlm.nih.gov/nuccore/NM_002485) |
| dbSNP | [rs1554555819](https://www.ncbi.nlm.nih.gov/snp/rs1554555819/) |
| Variant type | single nucleotide variant |
| Location | chr8:89943329-89943329 (GRCh38) |
| ClinVar | [VCV2106474](https://www.ncbi.nlm.nih.gov/clinvar/variation/2106474/) |

**All HGVS expressions:** `LRG_158:g.46343T>G`, `LRG_158t1:c.2108T>G`, `NC_000008.10:g.90955557A>C`, `NC_000008.11:g.89943329A>C`, `NG_008860.1:g.46343T>G`, `NM_001024688.3:c.1862T>G`, `NM_002485.5:c.2108T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9273)
- REVEL 0.872 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -5.165 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 11.033, GERP 1.79, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in NBN (of 1,266 modeled).
- CADD: **PHRED 24.4**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


Curated gene–disease validity (ClinGen):

- **Nijmegen breakage syndrome** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.83, 47% of residues very-high.

**5 experimental structure(s)** (PDB): [2ASK](https://www.rcsb.org/structure/2ASK), [2GH0](https://www.rcsb.org/structure/2GH0), [2GYR](https://www.rcsb.org/structure/2GYR), [2GYZ](https://www.rcsb.org/structure/2GYZ), [6Q2S](https://www.rcsb.org/structure/6Q2S).

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

*Describes the biological roles of NBN (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:** NBN's established molecular role includes growth factor activity.


### Pathways affected {#pathways}

NBN participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |

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

**Molecular function:** growth factor activity.

**Biological process:** glial cell-derived neurotrophic factor receptor signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-03.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-03-03 |

## Associated conditions {#conditions}

[Nijmegen breakage syndrome](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome/).

**Reported phenotype names (ClinVar):** Microcephaly, normal intelligence and immunodeficiency, IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY, Immunodeficiency, microcephaly with normal intelligence, BERLIN BREAKAGE SYNDROME, SEEMANOVA SYNDROME II, Ataxia telangiectasia variant V1, Nijmegen breakage syndrome, Microcephaly with normal intelligence immunodeficiency and lymphoreticular malignancies, Nonsyndromal microcephaly autosomal recessive with normal intelligence, Seemanova syndrome 2.

## Similar variants {#similar}

Related NBN variant pages (same residue, condition, or type): [NBN p.Ile703Thr](/variant/nbn-p-ile703thr), [NBN p.Ile703Val](/variant/nbn-p-ile703val), [NBN p.Ile703Phe](/variant/nbn-p-ile703phe), [NBN p.Ile703=](/variant/nbn-p-ile703), [NBN c.1124+1G>C](/variant/nbn-c-1124-plus-1g-c), [NBN c.1124+2T>G](/variant/nbn-c-1124-plus-2t-g), [NBN c.1397+2T>A](/variant/nbn-c-1397-plus-2t-a), [NBN c.171+1G>A](/variant/nbn-c-171-plus-1g-a).

### 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 2106474). 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.*