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): absent (AF=0) from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes.
No benign criterion marked as applied in the recorded assessment.
Variant of Uncertain Significance: only PM2 (Supporting) is met, and a single supporting criterion satisfies no pathogenic or benign combination under generic ACMG/AMP 2015.
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: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV58527414, n = 2 times).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 8 not met · 10 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP/CSPEC specification exists for NF2 (cspec.found=false, gene_vcep_dir=null, final_classification_framework.found=false); the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868) governs, per source_registry key generic_acmg_combination_rules.
All four segregation/de novo criteria (PS2, PM6, PP1, BS4) are not_assessed because the case bundle contains no proband, parental, trio, or family segregation data for NM_000268.3:c.363+1G>C.
The variant is absent from ClinVar (no submissions/classifications) and literature_pass.json retrieved 0 PMIDs with an empty criteria_index, so no source reports any de novo occurrence, meioses, segregation, or non-segregation for this exact variant.
The only variant-specific external hit, COSMIC COSV58527414 (somatic count 2), is somatic cancer data and is not usable for germline segregation/de novo criteria.
Sibling criteria (e.g., PVS1 via generic framework, population absence for PM2/BA1) are evaluated by other groups; this group only reports the absence of segregation/de novo evidence and defers classification impact to the final combination step.
No ClinGen CSPEC or local gene-specific framework exists for NF2 in this case (cspec.found=false, gene_vcep_dir=null, framework_mode=generic_acmg, final_classification_framework.found=false); generic ACMG/AMP 2015 (Richards et al., PMID:25741868) is the governing rule for PS3 and BS3.
The functional evidence base is empty: literature_pass.json found 0 PMIDs, fulltext_map.json is {}, there is no publications directory, and ClinVar has no record for NM_000268.3:c.363+1G>C.
PS3 is not_assessed: no well-established in vitro/in vivo functional study demonstrates a damaging effect on splicing or merlin function. SpliceAI (max delta 0.99, DS_DL 0.99) is an in silico prediction and must not be counted as PS3; COSMIC somatic occurrence (n=2) is not functional evidence.
BS3 is not_assessed: no functional study demonstrates absence of a damaging effect on splicing or protein function; the SpliceAI donor-loss prediction is directionally inconsistent with a benign functional outcome but is in silico only.
In silico splice prediction is not double-counted as functional evidence, consistent with the PVS1 assessment note that PP3 should not be stacked with PVS1 for the same splice-effect prediction.
Neither PS3 nor BS3 contributes to the final classification at this time; both remain open gaps pending functional assay data.
No CSPEC/VCEP specification exists for NF2 (cspec found=false; vcep_materials note 'no cspec url available'; final_classification_framework precedence_rank 3), so the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868) governs this case.
PS4 not met: no case-control or case-series enrichment data exists for c.363+1G>C; the variant is absent from ClinVar and the literature pass returned 0 PMIDs. The only report (COSMIC COSV58527414, n=2) is somatic cancer data and is not germline case-control evidence.
PP4 not assessed: the case bundle contains no proband phenotype or family-history data, which PP4 requires.
PP5 and BP6 not met: ClinVar has no record for the exact variant, so no exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic (PP5) or Benign/Likely benign (BP6) classification exists; ordinary laboratory submissions, aggregate labels, and non-expert assertions are excluded by group policy.
BP5 not assessed: no proband-level data demonstrating an alternate molecular basis of disease is available in the case bundle.
No ClinGen CSPEC/VCEP exists for NF2 and no local gene-specific framework was provided (vcep_materials.json: no cspec url, no user files), so generic ACMG/AMP 2015 (PMID:25741868) rules govern this group.
NF2-related schwannomatosis is an autosomal dominant tumor predisposition syndrome (germline monoallelic NF2 loss-of-function, per pvs1_gene_context.json literature evidence); therefore PM3, a recessive-disorder criterion requiring an in-trans pathogenic variant, is not applicable.
No allelic/phase evidence exists for c.363+1G>C: the variant is absent from ClinVar (no submissions), absent from gnomAD v2.1, v4.1, and gnomAD-Canada, no PMIDs were found in the literature pass, and fulltext_map.json is empty; BP2 cannot be assessed without proband/family cis-trans genotyping data.
The COSMIC somatic observation (COSV58527414, n=2) is somatic tumor data and was not used for germline allelic criteria PM3/BP2.
No NF2 CSPEC/VCEP or gene-specific PP3/BP4 lookup spreadsheet exists (cspec.found=false, gene_vcep_dir=null; vcep_materials.json: 'no cspec url available', files_found=[], summaries={}; final_classification_framework.json: found=false, precedence_rank=3, generic_acmg_fallback, scoring_model=ACMG/AMP 2015); generic ACMG/AMP 2015 (PMID:25741868, source_registry key generic_acmg_combination_rules) governs PP3/BP4.
Variant class: NM_000268.3:c.363+1G>C is a canonical +1 splice-donor variant (exon 3 donor; consequence_class=canonical_splice, canonical_splice_consensus=true, protein consequence p.?). BP7 (synonymous variants) is out of this variant's class and is not evaluated by this group.
PP3 is not awarded: SpliceAI max delta 0.99 confirms splice disruption, but c.363+1G>C is a canonical +1 splice-donor variant whose splice effect is already captured by PVS1 under the ClinGen SVI generic PVS1 framework (PMC6185798); pvs1_variant_assessment explicitly directs 'do not stack PP3 for the same splice-effect prediction evidence', so counting PP3 would double-count the same prediction.
BP4 is not met: both available computational lines (SpliceAI max delta 0.99; BayesDel 0.66) predict an impact; no benign-direction computational evidence exists.
BayesDel noAF 0.66 is a missense-calibrated predictor with unverified thresholds in this pipeline (REVEL is the verified calibration per PMID:36413997; BayesDel is not verified) and is off-label for an intronic canonical splice variant; it was not counted toward PP3 or BP4.
REVEL was not retrievable for this variant (prefetch.json steps.revel: found=false, revel_score=null); the missense in-silico path is empty because c.363+1G>C is intronic and outside the REVEL missense table.
No criterion was inferred from any external final classification: ClinVar has no submission for this variant (clinvar: search_status=no_result) and no VCEP pre-assignment exists.
This group contributes no supporting computational line (PP3 not met) and no benign computational line (BP4 not met) toward the final classification.
Population group assessment for NM_000268.3:c.363+1G>C (NF2): the variant is absent (AF=0) from gnomAD v2.1 exomes, gnomAD v4.1 exomes, and gnomAD-Canada v1.0 genomes, and has no ClinVar submissions.
No VCEP/CSPEC applies to NF2 in this case (framework_mode=generic_acmg, cspec found=false); generic ACMG/AMP 2015 (PMID:25741868) governs, with in-house non-VCEP gnomAD thresholds (PM2<0.1%, BS1>0.3%, BA1>1%).
BA1, BS1, and BS2 are not met: an AF of 0 cannot exceed any benign frequency threshold, and BS2 requires positive observation in healthy adults, which is absent.
PM2 is met at supporting strength (ClinGen SVI PM2_Supporting): absence from three independent large population datasets supports extreme rarity consistent with a pathogenic NF2 splice-donor variant.
Somatic COSMIC occurrence (COSV58527414, n=2) was reviewed and explicitly excluded from population reasoning; somatic tumor data is not germline population frequency evidence and cannot modify BA1/BS1/BS2/PM2.
No criteria match.
PM2 (Richards et al. 2015) is met when the variant is absent from controls (or at extremely low frequency) in population databases; the in-house non-VCEP threshold is PM2 when gnomAD AF <0.1%. NM_000268.3:c.363+1G>C is absent (AF=0) from gnomAD v2.1 exomes, gnomAD v4.1 exomes (~800k alleles), and gnomAD-Canada v1.0 genomes, consistent with the expected rarity of a pathogenic NF2 variant given an NF2-SWN incidence of 1 in 25,000-40,000 live births and a high de novo fraction. Strength is assigned as supporting (PM2_Supporting) per the ClinGen SVI PM2 recommendation, rather than the ACMG 2015 'moderate' default. No threshold artifact applies (absence is unambiguous). The COSMIC somatic count (n=2) does not contradict PM2 because it reflects tumor tissue, not germline population controls.
generic_acmg_2015 PM2 (SVI-adjusted supporting): absent in gnomAD (<0.1%) -> met, strength supporting
PS4 (Richards et al. 2015, PMID:25741868) requires the prevalence of the variant in affected individuals to be significantly increased compared with controls, i.e., exact-variant case-control enrichment or case-series data in the germline disease. No such data exists for NM_000268.3:c.363+1G>C: the variant is entirely absent from ClinVar (variation_ids empty, search_status 'no_result', zero submissions, clinvar_submission_audit.json = {}), the literature pass identified 0 PMIDs (literature_pass.json total_pmids = 0), and no case-control or case-series study reporting this variant was found. The only occurrence record is a somatic cancer entry in COSMIC (COSV58527414, somatic count n=2), which is somatic tumor data and cannot serve as germline case-control enrichment for NF2-related schwannomatosis. PS4 is not met: there is no enrichment signal of any kind for this variant.
PS4 (Richards et al. 2015, PMID:25741868): prevalence of the variant in affected individuals is significantly increased compared with controls; requires exact-variant case-control or case-series enrichment data.
PP3 (Richards et al. 2015, PMID:25741868) is met when multiple lines of computational evidence support a deleterious effect on the gene or gene product (including splicing impact). No NF2 CSPEC/VCEP or gene-specific PP3/BP4 lookup spreadsheet exists (cspec.found=false, gene_vcep_dir=null; vcep_materials.json: 'no cspec url available', files_found=[], summaries={}; final_classification_framework.json: found=false, precedence_rank=3, generic_acmg_fallback), so generic ACMG/AMP 2015 governs and would cap PP3 at supporting strength. The splice-impact line is decisive in direction: SpliceAI predicts near-certain splice disruption (max delta score = 0.99; DS_DL 0.99 donor loss at position +1, DS_DG 0.45 donor gain, DS_AL 0.23, DS_AG 0.0; variant_consequence=sequence_variant). However, NM_000268.3:c.363+1G>C is a variant at a canonical +1 splice-donor consensus position (consequence_class=canonical_splice, canonical_splice_consensus=true, exon 3 donor). Under the ClinGen SVI generic PVS1 framework (PMC6185798, source_registry key pvs1_generic_framework), canonical +/-1,2 splice variants are evaluated with PVS1 once germline loss of function is established, and the case's pvs1_variant_assessment (apply_generic_pvs1_framework=true, suggested_default_strength=PVS1) explicitly directs: 'For canonical splice variants, do not stack PP3 for the same splice-effect prediction evidence.' The SpliceAI prediction is exactly the same splice-effect evidence that underlies the PVS1 assignment; awarding PP3 here would double-count that prediction. BayesDel noAF = 0.66 is in the pathogenic direction but is a missense-calibrated predictor with unverified thresholds in this pipeline (REVEL is the verified calibration per PMID:36413997; BayesDel is not verified) and is off-label for an intronic splice-site variant; in any event it would only duplicate the same deleterious prediction already captured by PVS1. REVEL returned no score (intronic variant not covered by the missense REVEL table). PP3 is therefore not awarded to avoid double-counting the same splice-effect prediction.
Generic ACMG/AMP 2015 PP3 (Richards et al., PMID:25741868; source_registry key generic_acmg_combination_rules): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).' Supporting-strength ceiling under the generic framework. PP3 withheld per ClinGen SVI PVS1 guidance (PMC6185798, source_registry key pvs1_generic_framework) applied through pvs1_variant_assessment: for canonical +/-1,2 splice variants, the same splice-effect prediction evidence used for PVS1 must not be double-counted as PP3.
PP5 (Richards et al. 2015, PMID:25741868) applies when a reputable source recently reports the variant as pathogenic without evidence available for independent evaluation. Per this group's policy, PP5 is triggered ONLY by an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5. ClinVar contains no record at all for NM_000268.3:c.363+1G>C (variation_ids empty, review_status '', zero submissions, clinvar_submission_audit.json = {}), so no exact-variant expert-panel classification exists to support PP5. PP5 is not met.
PP5 (Richards et al. 2015, PMID:25741868) restricted by group policy: exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification required; supporting strength only.
BA1 (Richards et al. 2015, PMID:25741868) requires an allele frequency >5% (in-house non-VCEP gnomAD threshold >1%) in large population databases. NM_000268.3:c.363+1G>C in NF2 is absent from gnomAD v2.1 exomes (GRCh37 22-30035202-G-C), gnomAD v4.1 exomes (GRCh38 chr22-29639213-G-C), and gnomAD-Canada v1.0 genomes, i.e., allele frequency = 0 across all queried datasets. An AF of 0 cannot exceed any BA1 threshold; the criterion is therefore not met. No threshold-crossing artifact applies because the variant is absent rather than near a cutoff. Somatic occurrence in COSMIC (COSV58527414, n=2) is tumor data and is not population frequency evidence (see warnings).
generic_acmg_2015: BA1 AF>5% (in-house non-VCEP AF>1%); observed AF=0 -> not_met
BS1 (Richards et al. 2015) requires an allele frequency greater than expected for the disorder (in-house non-VCEP threshold >0.3%). NF2-related schwannomatosis (NF2-SWN) is a rare autosomal dominant tumor predisposition syndrome with an estimated incidence of 1 in 25,000-40,000 live births and a high proportion of de novo cases (>50%), so the expected allele frequency for a pathogenic NF2 variant is far below 0.1%. NM_000268.3:c.363+1G>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0), which is below, not above, the expected frequency for this disorder. BS1 is therefore not met.
generic_acmg_2015: BS1 AF>expected-for-disorder (in-house non-VCEP AF>0.3%); observed AF=0 -> not_met
BS2 (Richards et al. 2015) requires the variant to be observed in a healthy adult individual (heterozygous for an autosomal dominant disorder with full penetrance expected at an early age, or homozygous for a recessive disorder). NM_000268.3:c.363+1G>C is absent from all queried population cohorts (gnomAD v2.1, v4.1, gnomAD-Canada), so there are no healthy adult carriers and no homozygotes on record; the variant is also absent from ClinVar with no submissions. Absence of observations cannot satisfy a criterion that requires positive observation in healthy individuals; BS2 is not met. Note NF2-SWN penetrance is high but age-dependent (tumors typically manifest from the second/third decade onward), so an early-age full-penetrance interpretation would in any case be cautious.
generic_acmg_2015: BS2 requires observation in healthy adult (AD het / AR hom); zero observations -> not_met
BP4 (Richards et al. 2015, PMID:25741868) requires multiple lines of computational evidence suggesting no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Under the generic ACMG/AMP 2015 framework (no NF2 CSPEC/VCEP or local gene framework exists), the only available computational lines both predict an impact: SpliceAI max delta score = 0.99 (DS_DL 0.99 donor loss, DS_DG 0.45 donor gain) predicts strong splice disruption, and BayesDel noAF = 0.66 is in the pathogenic direction (missense-calibrated, unverified thresholds, so not treated as decisive, but it does not support no-impact either). There is no benign-direction computational line of any kind, and the variant sits at a canonical +1 splice-donor position where a no-impact call is not plausible. BP4 is not met.
Generic ACMG/AMP 2015 BP4 (Richards et al., PMID:25741868; source_registry key generic_acmg_combination_rules): 'Multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.).' Not met: every available computational line (SpliceAI max delta 0.99; BayesDel 0.66) predicts an impact and no benign-direction line exists.
BP6 (Richards et al. 2015, PMID:25741868) applies when a reputable source recently reports the variant as benign without evidence available for independent evaluation. Per this group's policy, BP6 is triggered ONLY by an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6. ClinVar contains no record for NM_000268.3:c.363+1G>C (variation_ids empty, review_status '', zero submissions, clinvar_submission_audit.json = {}), so no exact-variant expert-panel benign classification exists to support BP6. BP6 is not met.
BP6 (Richards et al. 2015, PMID:25741868) restricted by group policy: exact-variant ClinVar expert-panel Benign/Likely benign classification required; supporting strength only.
PVS1 could not be assessed because its agent did not produce valid output.
PS2 (ACMG/AMP 2015, Richards et al. PMID:25741868) requires a de novo occurrence in a proband with confirmed paternity and maternity. No proband, parental, or trio genotype data for NM_000268.3:c.363+1G>C is present anywhere in the case evidence bundle: the variant is absent from ClinVar (no submissions), literature_pass.json returned 0 PMIDs (criteria_index empty), fulltext_map.json is empty, and no family/pedigree data was captured in prefetch/evidence/case_summary. Without any proband or parental testing observation, PS2 cannot be met and cannot be formally ruled out; the criterion is therefore not assessed pending family segregation/testing data.
ACMG/AMP 2015 PS2 (de novo with confirmed parentage, strong) via generic_acmg_combination_rules
PS3 (Richards et al. 2015, PMID:25741868) requires well-established in vitro or in vivo functional studies demonstrating a damaging effect on the gene or gene product. For NF2 NM_000268.3:c.363+1G>C (canonical splice-donor +1 position) this means RNA-level evidence (patient RNA RT-PCR/cDNA analysis, minigene splicing assay, RNA-seq) or a protein-level (merlin) functional assay. No functional study of any kind is present for this variant: literature_pass.json reports 0 PMIDs, fulltext_map.json is empty, there is no publications directory, and ClinVar has no record (hence no submitter functional annotations). SpliceAI (max delta score 0.99, DS_DL 0.99) predicts loss of the donor site, but that is an in silico prediction, not a well-established functional study, and belongs to the PP3/BP4 evidence class under ACMG/AMP 2015. COSMIC reports 2 somatic occurrences (COSV58527414), which is tumor-occurrence data, not functional assay evidence. Because no functional evidence exists to evaluate, PS3 cannot be met or refuted and is returned not_assessed with the gap identified.
PS3 (Richards et al. 2015, PMID:25741868): 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product'; SVI PS3/BS3 calibration permits strong strength for well-established assays and supporting/moderate for limited or indirect assays - no functional assay of any kind is present here
PM6 (ACMG/AMP 2015) requires an assumed de novo occurrence without confirmation of paternity and maternity. No de novo occurrence of NM_000268.3:c.363+1G>C is reported in any consulted source: the variant is absent from ClinVar, no PMIDs were retrieved (literature_pass.json total_pmids=0), and no proband/parental testing data exists in the case bundle. In the absence of any observation of a de novo event (confirmed or assumed), PM6 is not assessed; the gap is absence of any proband-family genotype data rather than ambiguity in existing data.
ACMG/AMP 2015 PM6 (assumed de novo without confirmation of parentage, moderate) via generic_acmg_combination_rules
PP1 (ACMG/AMP 2015) requires cosegregation of the variant with disease in multiple affected family members in a gene definitively known to cause the disease. No segregation data (meioses, affected relatives tested, family pedigrees) for NM_000268.3:c.363+1G>C exists in the case bundle: the variant is absent from ClinVar, literature_pass.json returned 0 PMIDs, and no family/pedigree data was captured in prefetch/evidence/case_summary. NF2 is definitively known to cause NF2-related schwannomatosis, but without any observed segregating meioses PP1 cannot be applied; it is not assessed pending segregation data.
ACMG/AMP 2015 PP1 (cosegregation in multiple affected family members, supporting) via generic_acmg_combination_rules
PP4 (Richards et al. 2015, PMID:25741868) requires the proband's phenotype or family history to be highly specific for a disease with a single genetic etiology, and must be adjudicated on proband-level clinical data. The case bundle contains no clinical phenotype, pedigree, or family-history data for any proband carrying this variant (case_summary.json has no phenotype section; literature pass found 0 PMIDs; ClinVar has no record). Although NF2-related schwannomatosis phenotypes such as bilateral vestibular schwannomas are recognized as highly gene-specific, gene-level disease discussion in the PVS1 gene-context papers (e.g., PMID:41286393) does not mention this exact variant and cannot substitute for proband phenotype evidence. PP4 cannot be assessed without proband clinical data.
PP4 (Richards et al. 2015, PMID:25741868): phenotype or family history highly specific for a disease with a single genetic etiology.
BS3 (Richards et al. 2015, PMID:25741868) requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. No such functional evidence exists for NF2 NM_000268.3:c.363+1G>C: there are no functional studies in the evidence bundle (literature_pass.json 0 PMIDs, fulltext_map.json empty, no publications directory, ClinVar absent). The only variant-specific functional-relevant signal present, SpliceAI (max delta score 0.99, DS_DL 0.99), predicts loss of the canonical donor splice site and is directionally inconsistent with a 'no damaging effect on splicing' conclusion; however, an in silico prediction alone neither meets nor refutes BS3 in the absence of actual functional assay data. COSMIC somatic occurrence (n=2) does not establish normal function. Because no functional study demonstrating absence of a damaging effect is available, BS3 cannot be assessed and is returned not_assessed with the gap identified.
BS3 (Richards et al. 2015, PMID:25741868): 'Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing'; SVI PS3/BS3 calibration permits strong for well-established assays and supporting/moderate for limited assays - none present here
BS4 (ACMG/AMP 2015) requires absence of segregation (non-segregation) of the variant with disease in affected family members. No segregation or non-segregation observations exist for NM_000268.3:c.363+1G>C in any consulted source: the variant is absent from ClinVar, no PMIDs were retrieved (literature_pass.json total_pmids=0), and no family data is present in the case bundle. Because no affected family members were tested and no meioses were observed, BS4 cannot be met and cannot be excluded; the criterion is not assessed pending segregation data.
ACMG/AMP 2015 BS4 (non-segregation in affected family members, strong) via generic_acmg_combination_rules
BP2 requires a documented phase observation: the variant seen in trans with a pathogenic variant in a fully dominant disease/mechanism, or in cis with a pathogenic variant in any inheritance pattern. No such observation exists for NM_000268.3:c.363+1G>C. The variant is absent from ClinVar (no submissions), absent from gnomAD v2.1/v4.1/Canada, no literature PMIDs were identified in the literature pass, and the fulltext map is empty; no proband, family, segregation, or cis/trans phase data are available from any source. Evidence is insufficient to determine whether BP2 applies, so the criterion is not assessed pending genotypic/phase data.
Generic ACMG/AMP 2015 (PMID:25741868) BP2: 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.
BP5 (Richards et al. 2015, PMID:25741868) applies when the variant is found in a case with an alternate molecular basis for disease, requiring proband-level evidence that the phenotype is explained by a different molecular diagnosis. No proband-level clinical or molecular data exists in the case bundle for this variant (no ClinVar record, 0 PMIDs, no case data), so it cannot be determined whether any proband carrying this variant had an alternate molecular diagnosis. BP5 cannot be assessed.
BP5 (Richards et al. 2015, PMID:25741868): variant found in a case with an alternate molecular basis for disease.
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000268.3:c.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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_missense
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000268.3:c.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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_missense
PM3 applies only to recessive disorders, where the variant is detected in trans with a pathogenic variant in an affected individual. NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant tumor predisposition syndrome caused by monoallelic germline loss-of-function in the NF2 tumor suppressor gene (germline disease mechanism: dominant; biallelic inactivation occurs somatically as the second hit in tumors, which does not constitute recessive germline inheritance). No ClinGen CSPEC/VCEP or local gene-specific framework exists for NF2, so the generic ACMG/AMP 2015 rule applies, under which PM3 is not applicable to a fully dominant disease mechanism. Additionally, no genotype/phase data exist for this variant in any affected individual (absent from ClinVar; no literature PMIDs identified).
Generic ACMG/AMP 2015 (PMID:25741868) PM3: for recessive disorders, detected in trans with a pathogenic variant. Not applicable to autosomal dominant NF2-related schwannomatosis.
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.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. 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
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000268.3:c.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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_missense
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000268.3:c.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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_missense
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000268.3:c.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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_missense
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.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. 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.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. 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.
PP3 (Richards et al. 2015, PMID:25741868) is met when multiple lines of computational evidence support a deleterious effect on the gene or gene product (including splicing impact). No NF2 CSPEC/VCEP or gene-specific PP3/BP4 lookup spreadsheet exists (cspec.found=false, gene_vcep_dir=null; vcep_materials.json: 'no cspec url available', files_found=[], summaries={}; final_classification_framework.json: found=false, precedence_rank=3, generic_acmg_fallback), so generic ACMG/AMP 2015 governs and would cap PP3 at supporting strength. The splice-impact line is decisive in direction: SpliceAI predicts near-certain splice disruption (max delta score = 0.99; DS_DL 0.99 donor loss at position +1, DS_DG 0.45 donor gain, DS_AL 0.23, DS_AG 0.0; variant_consequence=sequence_variant). However, NM_000268.3:c.363+1G>C is a variant at a canonical +1 splice-donor consensus position (consequence_class=canonical_splice, canonical_splice_consensus=true, exon 3 donor). Under the ClinGen SVI generic PVS1 framework (PMC6185798, source_registry key pvs1_generic_framework), canonical +/-1,2 splice variants are evaluated with PVS1 once germline loss of function is established, and the case's pvs1_variant_assessment (apply_generic_pvs1_framework=true, suggested_default_strength=PVS1) explicitly directs: 'For canonical splice variants, do not stack PP3 for the same splice-effect prediction evidence.' The SpliceAI prediction is exactly the same splice-effect evidence that underlies the PVS1 assignment; awarding PP3 here would double-count that prediction. BayesDel noAF = 0.66 is in the pathogenic direction but is a missense-calibrated predictor with unverified thresholds in this pipeline (REVEL is the verified calibration per PMID:36413997; BayesDel is not verified) and is off-label for an intronic splice-site variant; in any event it would only duplicate the same deleterious prediction already captured by PVS1. REVEL returned no score (intronic variant not covered by the missense REVEL table). PP3 is therefore not awarded to avoid double-counting the same splice-effect prediction.
Generic ACMG/AMP 2015 PP3 (Richards et al., PMID:25741868; source_registry key generic_acmg_combination_rules): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).' Supporting-strength ceiling under the generic framework. PP3 withheld per ClinGen SVI PVS1 guidance (PMC6185798, source_registry key pvs1_generic_framework) applied through pvs1_variant_assessment: for canonical +/-1,2 splice variants, the same splice-effect prediction evidence used for PVS1 must not be double-counted as PP3.
BP4 (Richards et al. 2015, PMID:25741868) requires multiple lines of computational evidence suggesting no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Under the generic ACMG/AMP 2015 framework (no NF2 CSPEC/VCEP or local gene framework exists), the only available computational lines both predict an impact: SpliceAI max delta score = 0.99 (DS_DL 0.99 donor loss, DS_DG 0.45 donor gain) predicts strong splice disruption, and BayesDel noAF = 0.66 is in the pathogenic direction (missense-calibrated, unverified thresholds, so not treated as decisive, but it does not support no-impact either). There is no benign-direction computational line of any kind, and the variant sits at a canonical +1 splice-donor position where a no-impact call is not plausible. BP4 is not met.
Generic ACMG/AMP 2015 BP4 (Richards et al., PMID:25741868; source_registry key generic_acmg_combination_rules): 'Multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.).' Not met: every available computational line (SpliceAI max delta 0.99; BayesDel 0.66) predicts an impact and no benign-direction line exists.
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.363+1G>C in NF2 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000259.1:p.?. 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 possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
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 possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
This variant has previously been reported in somatic cancers (COSMIC; COSV58527414, n = 2 times).