No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.NF2 encodes Merlin, a scaffolding protein that links the cell's internal skeleton to the cell membrane and helps regulate cell growth, adhesion, and signaling. Loss of its function promotes tumor formation and spread. Germline mutations in this gene cause neurofibromatosis type 2, an inherited condition marked by tumors of the nervous system and skin, along with eye abnormalities. It acts as a tumor suppressor, and the gene is also found mutated in other types of cancer.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (Supporting): allele frequency is 0 — the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the <0.1% threshold.
No benign criterion marked as applied in the recorded assessment.
VUS: no ClinGen VCEP exists for NF2, so generic ACMG/AMP 2015 rules apply, and the single supporting criterion met (PM2, AF 0) reaches no combination threshold.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF2, a scaffolding protein, is frequently altered in mesothelioma, meningioma and nerve sheath tumors.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 13 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Framework: no ClinGen CSPEC/VCEP specification for NF2 was retrieved (cspec found=false; gene_vcep_dir null; vcep_materials 'no cspec url available'); generic ACMG/AMP 2015 (PMID 25741868) fallback applied (final_classification_framework precedence_rank 3, source 'generic_acmg_fallback').
Variant: NM_000268.3:c.1249A>T = NP_000259.1:p.(Ile417Phe), missense in NF2 exon 12; absent from ClinVar, gnomAD v2.1/v4.1/Canada, COSMIC, and all literature sources (0 PMIDs); SpliceAI max delta 0.02 (no splice impact).
PS1 not met: no established pathogenic variant producing p.Ile417Phe exists; c.1249A>T is the only single-nucleotide change capable of producing Phe at codon 417 (ATC>TTC).
PM1 not met: no mutational hotspot (Cancer Hotspots negative for NF2 I417; COSMIC absent) and no critical-domain evidence at residue 417; no gene-specific domain definition available.
PM5 not met: no same-residue comparator variants identified (pm5_candidates: 0 candidates, harvesting skipped, mode 'unknown'; ClinVar and literature empty). Flagged for human review due to skipped systematic same-residue search.
PP2 not met: NF2 germline mechanism is loss-of-function/truncating (not missense-common); missense constraint metric unavailable; low-rate-of-benign-missense prong unconfirmed.
BP1 not met: non-truncating NF2 alterations (in-frame deletions, etc.) are documented causes of NF2-related schwannomatosis (PMID:41565922), so the disease is not exclusively truncating.
Net contribution of this group: no evidence supporting any of PS1/PM1/PM5/PP2/BP1; all five criteria not met. The variant's missense nature at residue 417 contributes no codon-residue-domain evidence toward pathogenicity or benignity under the generic framework.
Governing framework: generic ACMG/AMP 2015 (Richards et al., PMID 25741868) via generic_acmg_combination_rules; no ClinGen CSPEC/VCEP specification exists for NF2 (cspec.found=false, gene_vcep_dir=null, final_classification_framework.found=false, source=generic_acmg_fallback), so no gene-specific adaptation of PS2/PM6/PP1/BS4 applies.
All four criteria in this group (PS2, PM6, PP1, BS4) are not_assessed because the case evidence bundle contains no proband, parental, or family/pedigree data of any kind: no de novo observation, no parentage confirmation, no segregation count, and no non-segregation observation.
Confirmatory negative findings: ClinVar has no submissions for NM_000268.3:c.1249A>T and literature_pass.json reports 0 PMIDs (fulltext_map.json is empty), so no external published de novo or segregation report for this variant exists to rescue any criterion in this group.
Per the evidence hierarchy, absence of segregation data (PP1) must not be interpreted as BS4, and absence of a reported de novo occurrence must not be interpreted as evidence against de novo status; all four criteria remain unevaluated pending clinical family data.
No ClinGen CSPEC/VCEP specification exists for NF2 (cspec.found=false, gene_vcep_dir=null, vcep_materials empty), so generic ACMG/AMP 2015 (PMID 25741868) governs PS3/BS3.
Variant is a missense substitution p.(Ile417Phe) in exon 12 of NF2; PS3/BS3 require well-established variant-specific functional assay data, none of which exist for this variant.
Literature pass returned 0 PMIDs and fulltext_map is empty; no publication was available or reviewed for the functional group.
Both PS3 and BS3 are returned as not_assessed because functional evidence is entirely absent - neither a deleterious nor a neutral functional effect can be established from the available data.
OncoKB's 'Unknown Oncogenic Effect' classification reflects absence of reviewed functional data and was not used to infer any criterion.
No ClinGen CSPEC/VCEP specification exists for NF2 (cspec.found = false; vcep_materials.json framework fallback 'generic_acmg_fallback', precedence rank 3); generic ACMG/AMP 2015 (source_registry generic_acmg_combination_rules, source_pmid 25741868) governs this group.
PS4, PP4, and BP5 are not_assessed: the variant has no reported carrier cases (ClinVar, COSMIC, and literature all empty) and no proband phenotype data exist in the case bundle, so case-control enrichment, phenotype specificity, and alternate-molecular-basis cannot be evaluated from available evidence.
PP5 and BP6 are not_met: the variant is entirely absent from ClinVar, so the required exact-variant expert-panel classification (Pathogenic/LP for PP5; Benign/LB for BP6) does not exist; non-expert and aggregate ClinVar labels are excluded by policy.
No criterion in this group contributes positive or negative evidence to the final classification; no strength assignments are made.
Framework: no CSPEC/VCEP or gene-specific framework was retrieved for NF2 (cspec found: false; final_classification_framework source: generic_acmg_fallback), so generic ACMG/AMP 2015 rules apply (generic_acmg_combination_rules, PMID 25741868).
PM3 - not_applicable: PM3 is a recessive-disorder criterion, and NF2-related schwannomatosis is autosomal dominant (PMID 41209567 full text: 'a rare autosomal dominant genetic disorder'). No trans-phase assessment is relevant to this disease context.
BP2 - not_met: the variant is absent from ClinVar and unreported in the literature (0 PMIDs); no observation of the variant in trans or cis with a pathogenic variant has been documented, so the BP2 trigger is unmet.
Allelic-group result: neither PM3 nor BP2 contributes evidence; final classification must rely on the other criteria groups.
PP3 not met: neither the splice path (SpliceAI max delta 0.02, below 0.2 per PMID 30661751) nor the missense path (REVEL 0.436, below PP3 supporting 0.644 per PMID 36413997) provides a line of computational evidence supporting a deleterious effect; BayesDel is excluded as insufficiently calibrated.
BP4 not met: only SpliceAI (max delta 0.02) provides a no-impact line; REVEL 0.436 is in the indeterminate zone and BayesDel is uncalibrated, so the multiple-lines requirement of BP4 is unsatisfied.
No NF2 CSPEC/VCEP specification exists; generic ACMG/AMP 2015 (PMID 25741868) governs PP3/BP4 adjudication for this case.
Population group adjudication under generic ACMG/AMP 2015 (PMID 25741868; no ClinGen CSPEC/VCEP for NF2, framework_mode=generic_acmg). NF2 c.1249A>T (p.Ile417Phe) is absent (AF=0) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. BA1 (AF>5%) and BS1 (AF greater than expected for a rare dominant disorder; local non-VCEP threshold >0.3%) are not met. BS2 is not met: there are zero healthy-adult carrier observations, and NF2-related schwannomatosis is adult-onset so the 'full penetrance at an early age' prerequisite is not satisfied. PM2 is met at supporting strength (AF=0, below the local non-VCEP <0.1% threshold), with moderate confidence due to binary-only gnomAD absence records (no AC/AN captured).
No criteria match.
PM2 (Richards et al. 2015, PMID 25741868) is met when a variant is absent (or at extremely low frequency) in population databases. c.1249A>T is absent (AF = 0) from gnomAD v2.1, gnomAD v4.1 (the largest reference exome dataset), and gnomAD-Canada v1.0, three independent population datasets spanning multiple ancestries. This is well below the local non-VCEP PM2 operating threshold of <0.1% and constitutes the strongest possible rarity evidence, supporting PM2 at supporting strength. Confidence is moderate rather than high because the evidence bundle records only binary absence status (source_data empty) without numeric allele counts (AC/AN) or per-population frequency breakdowns, and no additional datasets (e.g., TopMed) were queried. No VCEP specification exists for NF2, so generic ACMG/AMP 2015 applies.
generic_acmg_2015_pm2
PS1 (generic ACMG/AMP, PMID 25741868) requires a previously established pathogenic variant producing the same amino acid change. The variant NP_000259.1:p.(Ile417Phe) (c.1249A>T) has no ClinVar record (variation_ids empty, 'This variant is absent from ClinVar') and no literature reports (literature_pass: 0 PMIDs; fulltext_map empty). No established pathogenic variant producing p.Ile417Phe exists in any consulted source. Furthermore, codon 417 (ATC) can only produce Phe via the single-nucleotide change c.1249A>T, so no alternate-nucleotide same-amino-acid PS1 scenario is even possible. PS1 not met.
PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (Richards et al. 2015, PMID 25741868).
PM1 (generic ACMG/AMP, PMID 25741868) requires location in a mutational hotspot and/or a critical, well-established functional domain. No positive evidence places residue Ile417 in such a region: the Cancer Hotspots lookup for 'NF2 I417' returned no statistically significant hotspot; COSMIC has no record of c.1249A>T; no ClinGen CSPEC/VCEP specification defining NF2 hotspot/domain regions is available (generic fallback, final_classification_framework precedence_rank 3). OncoKB provides only gene-level tumor suppressor context with no domain annotation at residue 417 and no variant-specific functional evidence (classification 'Unknown Oncogenic Effect'). PM1 requires positive hotspot/domain evidence, which is absent; not met.
PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (Richards et al. 2015, PMID 25741868).
PM5 (generic ACMG/AMP, PMID 25741868) requires a different missense change at the same residue (Ile417) that is established as pathogenic. The pm5_candidates artifact found no same-residue candidates (pm5_mode 'unknown', eligible_for_classic_pm5_search false, total_candidates_seen 0, candidates []), and its recommendation states 'do not apply PM5 from this artifact alone'. The variant is absent from ClinVar and literature_pass identified 0 PMIDs, so no evidence of any established pathogenic missense at codon 417 exists in the case bundle. PM5 not met; flagged for human review because the systematic same-residue comparator search was skipped rather than performed.
PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (Richards et al. 2015, PMID 25741868).
PP2 (generic ACMG/AMP, PMID 25741868) requires BOTH a low rate of benign missense variation in the gene AND missense as a common mechanism of disease. Prong (a): no missense constraint metric (e.g., gnomAD missense Z-score / o/e) for NF2 was collected in this case, so it cannot be confirmed. Prong (b): the collected evidence supports loss-of-function as the characteristic germline mechanism of NF2-related schwannomatosis (pvs1_gene_context: lof_mechanism_supported true; PMID:41286393 'Genetic testing characteristically identifies a germline pathogenic variant (often truncating) in the NF2 gene'), and non-truncating variants are only part of a diverse spectrum (PMID:41565922). Missense is not established as a common disease mechanism for NF2. PP2 not met on available evidence.
PP2: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (Richards et al. 2015, PMID 25741868).
No calibrated computational evidence supports a deleterious effect for NF2 c.1249A>T (p.Ile417Phe). Splice path: SpliceAI max delta score is 0.02 (DS_DL 0.02; DS_AG/DS_AL/DS_DG 0.00), well below the 0.2 high-recall splice-alteration threshold (Jaganathan et al. 2019, PMID 30661751), so no splice impact is predicted for this exonic missense (exon 12, not near consensus splice sites). Missense path: REVEL score 0.436 is below the PP3 supporting threshold of 0.644 per the ClinGen SVI calibration (Pejaver et al. 2022, PMID 36413997), so it does not support PP3 (it also exceeds the BP4 supporting threshold of 0.291, i.e. indeterminate zone). BayesDel score -0.18104 cannot be used because no verified published PP3/BP4 threshold is available to this pipeline; it is treated as insufficiently calibrated and excluded per policy. With all available calibrated lines failing to reach the PP3 bar (and no other computational predictor data present), PP3 is not met. No VCEP/CSPEC specification exists for NF2, so the generic ACMG/AMP 2015 (PMID 25741868) definition was applied.
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): PP3 — multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). No NF2 CSPEC/VCEP specification exists (cspec found: false; final_classification_framework: generic_acmg_fallback).
Per governing instruction, PP5 may be applied only for an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ClinVar contains no record for c.1249A>T at all (variation_ids [], review_status '', submissions [], exact_match false; evidence_sentence 'This variant is absent from ClinVar.'). With no ClinVar entry, there is no expert-panel (3-star) classification that could support PP5, and ordinary laboratory/aggregate labels are excluded by policy in any case. PP5 is therefore definitively not met; no human review needed — the absence is unambiguous.
BA1 (Richards et al. 2015, PMID 25741868) requires an allele frequency >5% in a large reference population dataset (ESP, 1000 Genomes, ExAC/gnomAD). NF2 c.1249A>T (p.Ile417Phe) is absent (AF = 0) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, i.e., zero carriers in three independent population datasets. An AF of 0 is orders of magnitude below the >5% BA1 threshold, so BA1 is not met. Governing framework is generic ACMG/AMP 2015 (no ClinGen CSPEC/VCEP for NF2; framework_mode=generic_acmg).
generic_acmg_2015_ba1
BS1 (Richards et al. 2015, PMID 25741868) requires an allele frequency greater than expected for the disorder. NF2-related schwannomatosis (NF2-SWN) is a rare autosomal-dominant tumor predisposition syndrome (estimated incidence ~1 in 25,000-40,000 live births, >50% of cases de novo), so the expected allele frequency of pathogenic NF2 alleles is far below 0.1%. c.1249A>T is absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, which is far below the local non-VCEP BS1 operating threshold of >0.3% and below any plausible disease-expected frequency. BS1 is therefore not met. No VCEP specification exists for NF2, so the generic ACMG/AMP 2015 framework applies.
generic_acmg_2015_bs1
BS2 (Richards et al. 2015, PMID 25741868) requires observation of the variant in a healthy adult individual (heterozygous for a dominant disorder) where full penetrance is expected at an early age. c.1249A>T has zero observations in gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so there are no healthy-carrier observations to support BS2; absence cannot satisfy a criterion that requires a positive observation. Independently, NF2-related schwannomatosis is an adult-onset tumor predisposition syndrome (tumors typically developing from adolescence onward), so the BS2 prerequisite of 'full penetrance expected at an early age' is not satisfied for this disorder, meaning general-population adult carrier status would not be informative even if carriers existed. BS2 is not met.
generic_acmg_2015_bs2
BP1 (generic ACMG/AMP, PMID 25741868) requires that primarily/only truncating variants cause disease. NF2-related schwannomatosis is explicitly described as caused by diverse NF2 alterations including non-truncating variants (PMID:41565922: 'NF2-related schwannomatosis is a tumor predisposition syndrome caused by diverse NF2 alterations, including truncating variants, copy-number changes, and non-truncating variants such as in-frame indels'), and OncoKB gene background describes germline inactivation by 'mutation or deletion' broadly. The NF2 allelic disease spectrum is therefore not restricted to truncating alleles, and missense variants are not excluded as a cause. BP1 not met.
BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease (Richards et al. 2015, PMID 25741868).
BP2 requires a documented observation of the variant in trans with a pathogenic variant in a fully dominant disease, or in cis with a pathogenic variant in any inheritance pattern. No such observation exists for c.1249A>T (p.Ile417Phe): the variant is absent from ClinVar (no variation IDs; all search strategies returned no result), the case literature pass returned 0 PMIDs, and none of the retrieved NF2 gene-context papers mention c.1249A>T or p.Ile417. With no proband or family observations of this variant anywhere, no cis/trans phase configuration has been documented, so the BP2 observational trigger is not met and the criterion contributes no benign-supporting evidence.
BP2 (Richards et al. 2015, PMID 25741868): observed in trans with a pathogenic variant for a fully dominant disease/mechanism; or observed in cis with a pathogenic variant in any inheritance pattern.
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Only a single line is available: SpliceAI max delta 0.02 (< 0.2 threshold, Jaganathan et al. 2019, PMID 30661751) indicates no predicted splice impact. The missense predictors do not add a no-impact line: REVEL 0.436 lies in the indeterminate zone between the BP4 supporting threshold (0.291) and the PP3 supporting threshold (0.644) per ClinGen SVI calibration (Pejaver et al. 2022, PMID 36413997), and BayesDel (-0.18104) is excluded as insufficiently calibrated (no verified published threshold). With only one line of no-impact computational evidence, the multiple-lines requirement of BP4 is not satisfied, so BP4 is not met. No VCEP/CSPEC specification exists for NF2, so the generic ACMG/AMP 2015 (PMID 25741868) definition was applied.
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): BP4 — multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). No NF2 CSPEC/VCEP specification exists (cspec found: false; final_classification_framework: generic_acmg_fallback).
Per governing instruction, BP6 may be applied only for an exact-variant ClinVar expert-panel classification of Benign/Likely benign. ClinVar contains no record for c.1249A>T (variation_ids [], submissions [], exact_match false; evidence_sentence 'This variant is absent from ClinVar.'). No ClinVar entry exists, hence no expert-panel Benign/Likely benign classification is available, and non-expert or aggregate labels are excluded by policy in any case. BP6 is therefore definitively not met; the absence is unambiguous and requires no human review.
PS2 (de novo with confirmed parentage) cannot be evaluated: the case evidence bundle contains no proband-level data whatsoever. There is no proband genotype result, no parental testing, no maternity/paternity confirmation, and no documentation of the proband's phenotype or family history. ClinVar has zero submissions for NM_000268.3:c.1249A>T (evidence.json clinvar: search_status no_result), so no published de novo occurrence of this variant exists to consult. With no de novo observation, PS2 is not supported by any available evidence.
PS2 - De novo (paternity and maternity confirmed) occurrence of the variant in a patient with the disease and no family history (Richards et al. 2015, PMID 25741868)
No well-established functional studies of this variant are available in any evidence source. The variant is a missense change, NF2 (NM_000268.3):c.1249A>T p.(Ile417Phe) (exon 12), and no variant-specific functional assay data were identified: (1) literature_pass.json returned 0 PMIDs and fulltext_map.json is empty, so no publications were available for functional review; (2) ClinVar has no entry for this variant, hence no submitted functional evidence; (3) OncoKB (oncokb) explicitly reports no variant-specific reviewed functional evidence for p.Ile417Phe (classification 'Unknown Oncogenic Effect', is_variant_specific=false, not_reviewed=true) and provides gene-level context only; (4) COSMIC has no somatic record, which addresses somatic recurrence rather than functional effect. In silico scores (REVEL 0.436, BayesDel -0.18104) and SpliceAI (max delta 0.02) are predictive tools, not well-established functional assays, and cannot satisfy PS3 per ACMG/AMP 2015 (PMID 25741868). PS3 is therefore not assessed pending functional assay data (e.g., merlin localization/growth-suppression or other validated NF2 functional assays).
PS3: Well-established functional studies show a deleterious effect (generic ACMG/AMP 2015, PMID 25741868; no NF2 ClinGen CSPEC/VCEP specification available).
Generic ACMG/AMP 2015 governs this case because no ClinGen CSPEC/VCEP specification exists for NF2 (vcep_materials.json: framework fallback 'generic_acmg_fallback', precedence rank 3, scoring model ACMG/AMP 2015; cspec.found = false). PS4 requires the variant to be significantly enriched in affected individuals versus controls in case-control or cohort data. No such data exist for c.1249A>T: the variant is absent from ClinVar (no submissions, no reported cases), absent from gnomAD v2.1, v4.1 and gnomAD-Canada v1.0 (no population allele frequency in controls), absent from COSMIC (no somatic reports), and literature_pass.json identified 0 PMIDs (no case series or association studies retrieved). With no affected case ever reported, PS4 is not met, but the total absence of any prevalence study means the criterion is unassessable from available evidence rather than affirmatively refuted; a diagnostic NF2/schwannomatosis cohort study would be required to evaluate it.
PM6 (assumed de novo without confirmed parentage) cannot be evaluated: the evidence bundle contains no observation of the variant arising de novo in any proband, with or without parental testing. There is no proband or family genotype data in any bundle artifact (case_summary.json, evidence.json, prefetch.json, literature_pass.json, fulltext_map.json), and literature_pass.json reports 0 PMIDs across all evidence sources. Absence of any de novo observation means PM6 has no evidentiary basis.
PM6 - Assumed de novo occurrence of the variant in a patient with the disease, but without confirmation of paternity and maternity (Richards et al. 2015, PMID 25741868)
PP1 (co-segregation with disease in multiple affected family members) cannot be evaluated: no family/pedigree data is present anywhere in the case evidence bundle. There are no affected family members tested, no meioses observed, and no segregation analysis available. The generic ACMG/AMP 2015 framework (Richards et al. 2015, PMID 25741868) requires at least one informative segregation observation among multiple affected relatives; zero segregation data points are available here.
PP1 - Co-segregation of the variant with disease in multiple affected family members in a gene definitively known to cause the disease (Richards et al. 2015, PMID 25741868)
PP4 requires the variant to be observed in a proband whose phenotype or family history is highly specific for a gene with a single genetic etiology. The case bundle contains no proband phenotype information whatsoever: case_summary.json contains no clinical phenotype, family history, tumor history, or segregation description, and no literature source reports this variant in any patient (literature_pass total_pmids = 0; publications directory empty; fulltext_map.json {}). Phenotype specificity therefore cannot be evaluated. Note the variant's gene context (NF2-related schwannomatosis, bilateral vestibular schwannomas, meningiomas) is well established, but PP4 applies to the variant carrier's phenotype, which is absent here.
No functional studies demonstrating an absence of damaging effect are available. SpliceAI (spliceai) predicts no significant splice impact for c.1249A>T (max delta score 0.02; DS_AG/AL/DG 0.0, DS_DL 0.02), but this is an in silico prediction and not a well-established functional assay (e.g., RT-PCR/minigene splicing assay or protein function assay), so it is insufficient for BS3 under ACMG/AMP 2015 (PMID 25741868). Absence from gnomAD (gnomad_v2, gnomad_v4, gnomad_canada) is population-frequency evidence relevant to PM2/BS1/BA1, not a functional assay, and does not inform BS3. OncoKB provides no variant-specific functional data that could establish a neutral effect. BS3 is therefore not assessed pending functional assay evidence showing wild-type-like protein/splicing function.
BS3: Well-established functional studies show no damaging effect on protein function or splicing (generic ACMG/AMP 2015, PMID 25741868; no NF2 ClinGen CSPEC/VCEP specification available).
BS4 (lack of segregation in affected family members) cannot be evaluated: the evidence bundle contains no family/pedigree data at all. There are no affected family members genotyped, so there is no observation of an affected individual lacking the variant, which is the minimum requirement for BS4. Absence of evidence of segregation cannot be equated with evidence of non-segregation.
BS4 - Lack of segregation of the variant with disease in affected family members (Richards et al. 2015, PMID 25741868)
BP5 applies when the variant is found in a case with an established alternate molecular basis of disease (e.g., a clearly pathogenic variant in another gene, or a different confirmed cause). No case-level data exist for c.1249A>T: the variant has never been reported in any affected individual (ClinVar absent, literature_pass 0 PMIDs), so there is no proband in whom an alternate molecular basis could be identified or excluded. The criterion is therefore unassessable from available evidence; it cannot be met or refuted without a reported carrier case.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000268.3:c.1249A>T in NF2 is a missense substitution predicted to produce NP_000259.1:p.(Ile417Phe). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM3 applies only to recessive disorders (variant detected in trans with a pathogenic variant in a recessive disease). NF2-related schwannomatosis (NF2-SWN, formerly neurofibromatosis type 2) is an autosomal dominant tumor predisposition syndrome; the gene-context literature retrieved for this case explicitly describes it as 'a rare autosomal dominant genetic disorder' (PMID 41209567, full text, Introduction). The disease model is a heterozygous germline NF2 pathogenic variant plus a somatic second hit in tumors (two-hit mechanism); a biallelic germline recessive mechanism is not part of the disease model. Because PM3 is definitionally restricted to recessive disease contexts, it is not applicable here regardless of any trans-phase observation, so no trans assessment was performed.
PM3 (Richards et al. 2015, PMID 25741868): for recessive disorders, detected in trans with a pathogenic variant. Restricted to recessive disease contexts; NF2-related schwannomatosis is autosomal dominant, so the criterion is inapplicable.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000268.3:c.1249A>T in NF2 is a missense substitution predicted to produce NP_000259.1:p.(Ile417Phe). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000268.3:c.1249A>T in NF2 is a missense substitution predicted to produce NP_000259.1:p.(Ile417Phe). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000268.3:c.1249A>T in NF2 is a missense substitution predicted to produce NP_000259.1:p.(Ile417Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in NF2, mapped onto the exon structure of NM_000268.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
No calibrated computational evidence supports a deleterious effect for NF2 c.1249A>T (p.Ile417Phe). Splice path: SpliceAI max delta score is 0.02 (DS_DL 0.02; DS_AG/DS_AL/DS_DG 0.00), well below the 0.2 high-recall splice-alteration threshold (Jaganathan et al. 2019, PMID 30661751), so no splice impact is predicted for this exonic missense (exon 12, not near consensus splice sites). Missense path: REVEL score 0.436 is below the PP3 supporting threshold of 0.644 per the ClinGen SVI calibration (Pejaver et al. 2022, PMID 36413997), so it does not support PP3 (it also exceeds the BP4 supporting threshold of 0.291, i.e. indeterminate zone). BayesDel score -0.18104 cannot be used because no verified published PP3/BP4 threshold is available to this pipeline; it is treated as insufficiently calibrated and excluded per policy. With all available calibrated lines failing to reach the PP3 bar (and no other computational predictor data present), PP3 is not met. No VCEP/CSPEC specification exists for NF2, so the generic ACMG/AMP 2015 (PMID 25741868) definition was applied.
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): PP3 — multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). No NF2 CSPEC/VCEP specification exists (cspec found: false; final_classification_framework: generic_acmg_fallback).
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. Only a single line is available: SpliceAI max delta 0.02 (< 0.2 threshold, Jaganathan et al. 2019, PMID 30661751) indicates no predicted splice impact. The missense predictors do not add a no-impact line: REVEL 0.436 lies in the indeterminate zone between the BP4 supporting threshold (0.291) and the PP3 supporting threshold (0.644) per ClinGen SVI calibration (Pejaver et al. 2022, PMID 36413997), and BayesDel (-0.18104) is excluded as insufficiently calibrated (no verified published threshold). With only one line of no-impact computational evidence, the multiple-lines requirement of BP4 is not satisfied, so BP4 is not met. No VCEP/CSPEC specification exists for NF2, so the generic ACMG/AMP 2015 (PMID 25741868) definition was applied.
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): BP4 — multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). No NF2 CSPEC/VCEP specification exists (cspec found: false; final_classification_framework: generic_acmg_fallback).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000268.3:c.1249A>T in NF2 is a missense substitution predicted to produce NP_000259.1:p.(Ile417Phe). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.436. BayesDel score = -0.18104.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.436. BayesDel score = -0.18104.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF2, a scaffolding protein, is frequently altered in mesothelioma, meningioma and nerve sheath tumors.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.