Classification rationale

PVS1PM2 BP4 VUS

NF2 c.778G>T nonsense · exon 8

PVS1 (Very Strong): nonsense variant p.(Glu260Ter) predicted to trigger nonsense-mediated decay, consistent with a null NF2 allele. PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases. BP4 (Supporting): SpliceAI max delta 0.149 below the ~0.2 cutoff predicts no significant splice disruption. Final classification: VUS - the combination of PVS1 (very strong) and PM2 (supporting) for pathogenicity against BP4 (supporting) for benignity leaves conflicting evidence under the generic ACMG/AMP 2015 rules.

PVS1 + PM2 + BP4 → VUS

Gene diagram · NM_000268.3 · variants mapped to exon structure

NF2 NM_000268.3

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met (Very Strong): the nonsense variant p.(Glu260Ter) is predicted to trigger nonsense-mediated decay, consistent with a null NF2 allele.

case_summary.json cspec.found=false and vcep_materials.final_classification_framework.found=false confirm no NF2-specific VCEP PVS1 specification is available, mandating generic ACMG/AMP PVS1 fallback per PMC6185798 (pvs1_variant_assessment.framework_source).pvs1_gene_context.json: lof_mechanism_supported=true and pvs1_gene_gate='eligible', with mechanism_rationale stating that targeted germline literature review identified disease-focused publications supporting NF2 loss of function as a germline disease mechanism.pvs1_variant_assessment.json: consequence_class='nonsense', variant_bucket='nonsense', protein_1l='NP_000259.1:p.(E260*)', suggested_default_strength='PVS1', with rationale that nonsense variants are evaluated with the generic PVS1 framework once germline LOF is established.

pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

The case bundle reports NM_000268.3:c.778G>T as absent from gnomAD v2.1.The case bundle reports NM_000268.3:c.778G>T as absent from gnomAD v4.1.The case bundle reports NM_000268.3:c.778G>T as absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (Supporting): SpliceAI max delta 0.149 is below the ~0.2 cutoff, predicting no significant splice disruption.

SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15).' Scores: DS_AG=0.0, DS_AL=0.149, DS_DG=0.006, DS_DL=0.035; max_delta_score=0.149, below the ~0.2 SpliceAI delta-score threshold associated with likely splice-altering effects.BayesDel score 0.66 (local BayesDel_170824_noAF lookup) not used because no verified published calibration threshold/PMID for BayesDel is available to this pipeline.REVEL not available for this position (revel_score null).

spliceai ↗

Assessed · not applied · 3 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no confirmed de novo occurrence is documented; parental testing and phenotype information were not available.

PS3 Not assessed: no validated functional assay specific to this variant was available.

PS4 Not assessed: no affected-case counts, controls, or variant-specific case series were available.

PM6 Not assessed: no parental testing or case-level information supporting a de novo occurrence was available.

PP1 Not assessed: no family segregation data or informative meioses were available.

PP3 Not met: SpliceAI max delta 0.149 is below the ~0.2 cutoff for a likely splice-altering effect.

PP4 Not assessed: no patient phenotype or clinical diagnostic criteria were available to evaluate phenotype specificity.

PP5 Not assessed: no ClinVar expert-panel pathogenic classification is documented for this exact variant.

Benign

BA1 Not met: the variant is absent from population databases, so no allele frequency reaches the standalone benign threshold.

BS1 Not met: the variant is absent from population datasets, so no allele frequency exceeds the expected rate for NF2-related disease.

BS2 Not assessed: no healthy-adult cohort or unaffected-control observation of this variant was available.

BS3 Not assessed: no functional assay evidence of a benign effect for this specific variant was available.

BS4 Not assessed: no unaffected relatives with reliable genotypes were available to demonstrate lack of segregation.

BP2 Not assessed: no second variant or phase information was available to evaluate trans configuration.

BP5 Not assessed: no evidence that the phenotype is explained by an alternative molecular cause was available.

BP6 Not assessed: no ClinVar expert-panel benign classification is documented for this exact variant.

N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). BayesDel score = 0.66.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 4 PMIDs not cited in assessment

19545378 ↗ Neurofibromatosis type 2 (NF2): a clinical and molecular review. ONCOKB

22825583 ↗ New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. ONCOKB

8755919 ↗ Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. ONCOKB

9643284 ↗ Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. ONCOKB