# NM_000834.5(GRIN2B):c.2674_2698dup (p.Arg900fs)

https://sugi.bio/variant/grin2b-p-arg900fs

## Summary

**GRIN2B p.Arg900fs (c.2674_2698dup)** is classified **Likely pathogenic** in GRIN2B (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-01). No gnomAD frequency available for this variant.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2136406273 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the GRIN2B gene that is considered likely disease-causing, 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 | [GRIN2B](https://sugi.bio/atlas/gene/GRIN2B/) |
| Protein change (HGVS p.) | p.Arg900fs |
| Coding change (HGVS c.) | c.2674_2698dup |
| MANE Select transcript | [NM_000834](https://www.ncbi.nlm.nih.gov/nuccore/NM_000834) |
| dbSNP | [rs2136406273](https://www.ncbi.nlm.nih.gov/snp/rs2136406273/) |
| Variant type | Duplication |
| Location | chr12:13564539-13564540 (GRCh38) |
| ClinVar | [VCV1298535](https://www.ncbi.nlm.nih.gov/clinvar/variation/1298535/) |

**All HGVS expressions:** `NC_000012.11:g.13717474_13717498dup`, `NC_000012.12:g.13564540_13564564dup`, `NG_031854.2:g.422449_422473dup`, `NM_000834.5:c.2674_2698dup`

## 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 7.667, GERP 0.692, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.102, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (14 of 14)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- 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.
- 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}

**GRIN2B** population constraint: LOEUF 0.102, pLI 1, missense-Z 7.3414; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **complex neurodevelopmental disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 60.66, 18% of residues very-high.

**36 experimental structure(s)** (PDB): [10EX](https://www.rcsb.org/structure/10EX), [10EY](https://www.rcsb.org/structure/10EY), [10EZ](https://www.rcsb.org/structure/10EZ), [10FD](https://www.rcsb.org/structure/10FD), [10FE](https://www.rcsb.org/structure/10FE), [10FF](https://www.rcsb.org/structure/10FF).

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

*Describes the biological roles of GRIN2B (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:** GRIN2B's established molecular role includes NMDA glutamate receptor activity.


### Pathways affected {#pathways}

GRIN2B participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Synaptic adhesion-like molecules](https://reactome.org/content/detail/R-HSA-8849932) | curated |
| [Activated NTRK2 signals through FYN](https://reactome.org/content/detail/R-HSA-9032500) | electronic |
| [Assembly and cell surface presentation of NMDA receptors](https://reactome.org/content/detail/R-HSA-9609736) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [Long-term potentiation](https://reactome.org/content/detail/R-HSA-9620244) | electronic |
| [MECP2 regulates neuronal receptors and channels](https://reactome.org/content/detail/R-HSA-9022699) | electronic |
| [Negative regulation of NMDA receptor-mediated neuronal transmission](https://reactome.org/content/detail/R-HSA-9617324) | electronic |
| [Neurexins and neuroligins](https://reactome.org/content/detail/R-HSA-6794361) | electronic |
| [Ras activation upon Ca2+ influx through NMDA receptor](https://reactome.org/content/detail/R-HSA-442982) | electronic |
| [Unblocking of NMDA receptors, glutamate binding and activation](https://reactome.org/content/detail/R-HSA-438066) | electronic |

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

**Molecular function:** NMDA glutamate receptor activity, glycine binding, glutamate-gated calcium ion channel activity, ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential.

**Biological process:** response to ethanol, calcium ion transmembrane import into cytosol, monoatomic cation transmembrane transport.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-08-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-08-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related GRIN2B variant pages (same residue, condition, or type): [GRIN2B p.Arg900Cys](/variant/grin2b-p-arg900cys), [GRIN2B p.Arg900His](/variant/grin2b-p-arg900his), [GRIN2B p.Arg900=](/variant/grin2b-p-arg900), [GRIN2B c.1125+6_1125+10dup](/variant/grin2b-c-1125-plus-6-1125-plus-10dup), [GRIN2B c.1655-12dup](/variant/grin2b-c-1655-minus-12dup), [GRIN2B c.2011-2_2038dup](/variant/grin2b-c-2011-minus-2-2038dup), [GRIN2B c.2352_2359+2dup](/variant/grin2b-c-2352-2359-plus-2dup), [GRIN2B p.Glu500_Val501insProGlyMetValTer](/variant/grin2b-p-glu500-val501insproglymetvalter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1298535). 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.*