Is NBN p.Glu658fs (c.1974del) pathogenic?

NBN p.Glu658fs (c.1974del) is classified Pathogenic/Likely pathogenic in NBN (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-02-14). Very rare (popmax 8.64e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with NBN p.Glu658fs (c.1974del)?

NBN p.Glu658fs (c.1974del) is associated with hereditary neoplastic syndrome, Nijmegen breakage syndrome, aplastic anemia (ClinVar).

How common is NBN p.Glu658fs (c.1974del) in the general population?

NBN p.Glu658fs (c.1974del) is very rare (popmax 8.64e-05%, nfe) (gnomAD).

NBN p.Glu658fs

c.1974del · rs1057516668 · VCV370663

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.64e-05%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.64e-05% European (non-Finnish) · 1/1,157,460 alleles

Overall 6.96e-05% 1/1,436,732 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NBN
Protein: p.Glu658fs
Coding: c.1974del
MANE Select: NM_057091 · reported on NM_002485
dbSNP: rs1057516668
Type: Deletion
Location: chr8:89946236 (GRCh38)
Structure: AlphaFold pLDDT 75.83 · 5 PDB

Full NBN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Nijmegen breakage syndrome aplastic anemia

Similar variants

NBN p.Glu658Gly Uncertain significance ★★ same residue
NBN p.Glu658Asp Uncertain significance ★ same residue
NBN c.1397+1_1397+9del Likely pathogenic ★★ same condition
NBN c.1397+1del Pathogenic ★★ same condition
NBN c.163_171+3del Pathogenic/Likely pathogenic ★★ same condition
NBN c.2070+2del Likely pathogenic ★★ same condition
NBN c.2071del Pathogenic/Likely pathogenic ★★ same condition
NBN c.2226_2234+4del Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nbn-p-glu658fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown