Classification rationale

PVS1PM2 BP4 VUS

NF2 c.958C>T nonsense · exon 10

PVS1 (Very Strong): the p.Gln320Ter premature stop codon lies ~780 nucleotides upstream of the final exon-exon junction, predicting nonsense-mediated decay. PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. BP4 (Supporting): SpliceAI max delta 0.003 predicts no splice disruption. Overall: VUS - PVS1 (very strong) and PM2 (supporting) would reach likely pathogenic, but conflicting BP4 (supporting) holds the result at VUS.

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: the p.Gln320Ter premature stop codon lies ~780 nucleotides upstream of the final exon-exon junction, well beyond the ~50-nucleotide threshold for nonsense-mediated decay.

pvs1_variant_assessment: transcript NM_000268.3:c.958C>T, protein NP_000259.1:p.(Gln320Ter), consequence_class=nonsense, variant_bucket=nonsense, generic PVS1 framework applies per PMC6185798 (framework_source https://pmc.ncbi.nlm.nih.gov/articles/PMC6185798/).VariantValidator exon/CDS map (bundle prefetch): exon10 boundaries c.886-999 (variant c.958 falls inside), 16 total coding exons, last exon begins at c.1738, CDS c.1-1788; places the PTC ~780 nt upstream of the final exon-exon junction, well beyond the ~50 nt NMD-escape threshold, so NMD is predicted.VariantValidator protein prediction: position_last_original=596 (full-length merlin), position_last_predicted=320, i.e. the truncation removes 277 of 596 residues (~46%) if NMD were escaped, supporting a clinically significant truncation regardless.

pvs1_generic_framework ↗spliceai ↗

✓

PM2 supporting Pathogenic

Met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

The case bundle reports the exact variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.The NF2 clinical and molecular review describes NF2 as a dominantly inherited tumor-prone disorder and states that disease prevalence has risen to around 1 in 60,000; this supports the rare-disease context for evaluating absence from population controls.No population database reported a homozygote or a nonzero ancestry-specific frequency for this variant.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:19545378 ↗

✓

BP4 supporting Benign

Met: SpliceAI max delta 0.003 is far below the ~0.2 splice-altering threshold, predicting no splice impact.

SpliceAI (case_summary.json compact_evidence.spliceai): max delta score = 0.003 (DS_AG=0.001, DS_AL=0.001, DS_DG=0.0, DS_DL=0.003) for NM_000268.3:c.958C>T, below the ~0.2 splice-altering threshold from the original SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), supporting no predicted splicing impact.

spliceai ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no parental testing results or documented de novo observation were available.

PS3 Not assessed: no functional assay data for this variant were available.

PS4 Not assessed: no case series or case-control comparison demonstrating increased prevalence in affected individuals was available.

PM6 Not assessed: no unconfirmed de novo observation was documented.

PP1 Not assessed: no affected relatives, segregation data, or informative meioses were provided.

PP3 Not met: SpliceAI max delta 0.003 predicts no splice disruption, and no other computational evidence supports a damaging effect.

PP4 Not assessed: no patient-specific phenotype data were available to confirm a highly specific NF2 presentation.

PP5 Not met: no expert-panel ClinVar submission exists for this variant, and laboratory or OMIM classifications cannot trigger PP5.

Benign

BA1 Not met: the variant is absent from population databases, far below any stand-alone benign frequency threshold.

BS1 Not met: the variant is absent from population databases, below the disease-specific maximum credible allele frequency.

BS2 Not assessed: no evidence of occurrence in healthy adults or homozygous individuals was provided.

BS3 Not assessed: no functional assay evidence of normal activity was available.

BS4 Not assessed: no unaffected relatives or non-segregation analysis was reported.

BP2 Not assessed: no second variant or phase determination was available to assess allelic arrangement.

BP5 Not assessed: insufficient evidence linked this variant to an alternate phenotype or disease mechanism.

BP6 Not met: no expert-panel ClinVar classification of Benign or Likely benign exists for this 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 has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 3291)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). 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 previously been reported in somatic cancers (COSMIC; COSV58522975, n = 4 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

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

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

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

7913580 ↗ Mutational analysis of patients with neurofibromatosis 2. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR