No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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 (very strong): Nonsense change p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay.
Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, three large population cohorts, in a gene with an established loss-of-function disease mechanism.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PVS1 very strong (nonsense p.Ser288Ter) plus PM2 supporting (absent from gnomAD) yields Likely Pathogenic under generic ACMG/AMP 2015 (ClinGen SVI 2020, posterior 0.988), with no conflicting evidence.
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: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV58523216, n = 10 times).
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: 2 met · 8 not met · 7 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 (Very Strong): c.863C>G creates a premature termination codon (p.Ser288Ter) in exon 9/16 of the NF2 canonical transcript; NF2 haploinsufficiency/LoF is an established germline disease mechanism; the truncation is NMD-expected and removes ~52% of the protein, including most of the FERM domain and the entire C-terminal half of merlin.
No exon-level or variant-level downgrade applies: the variant is absent from gnomAD v2.1/v4.1/Canada, exon 9 is not a terminal or LoF-enriched exon, and SpliceAI predicts no splice impact (max delta 0.00), so the variant is a pure nonsense null allele.
Variant-level PVS1 determination relies on sequence-consequence and gene-mechanism evidence only; the single-submitter ClinVar Pathogenic classification (SCV001190519) was not used to support PVS1.
No VCEP/CSPEC specification exists for NF2 (cspec found=false, framework_complete=false); the generic ACMG/AMP 2015 framework (PMID:25741868) governs this case.
The case evidence bundle contains no proband, parental, or family genotype data for NM_000268.3:c.863C>G; none of the four segregation/de novo criteria (PS2, PM6, PP1, BS4) can be evaluated on available evidence and all are returned as not_assessed.
The single ClinVar germline submission (SCV001190519) reports Pathogenic without listing any criteria; per adjudication rules its final classification is not used to infer any segregation or de novo criterion.
No ClinGen CSPEC/VCEP specification for NF2 was available (cspec found=false; vcep_materials.json empty; final_classification_framework found=false, precedence_rank 3, framework_mode generic_acmg), so PS3 and BS3 were adjudicated under the generic ACMG/AMP 2015 framework (PMID:25741868) per the generic_acmg_combination_rules fallback.
PS3 not_assessed: the criterion requires well-established functional studies showing a deleterious effect; none exist for this exact variant. The only variant-specific functional-adjacent items (OncoKB curated 'Likely Loss-of-function' label; COSMIC somatic recurrence n=10) are curation/observation, not validated assays, and none of the available full-text publications mention c.863C>G/p.Ser288Ter (verified by full-text search). Per the 'insufficient evidence -> not_assessed' rule, PS3 remains not_assessed pending a variant-specific validated functional assay; strength cannot be calibrated.
BS3 not_assessed: no functional studies demonstrate absence of a damaging effect on protein function or splicing; SpliceAI (max delta 0.00) is in silico and does not qualify, and all directional evidence (nonsense truncation at residue 288 of 596, OncoKB LOF curation, COSMIC recurrence, gene-level truncation severity data in PMID:9643284) points toward a damaging effect. BS3 remains not_assessed pending validated functional data.
The truncating nature of this variant is accounted for under PVS1 (separate consequence/loss-of-function group); PS3 was not stacked on the same truncation evidence to avoid double-counting the same functional consequence.
ClinVar's Pathogenic classification (1-star, criteria provided/single submitter) was not used as PS3/BS3 evidence because a source's final classification is not criterion-level evidence.
No ClinGen CSPEC/VCEP and no local custom gene framework exists for NF2 (cspec.found=false, gene_vcep_dir=null, framework_mode=generic_acmg, precedence_rank=3); the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868) governs all criteria in this group.
PS4 not met: no case-control or cohort prevalence data for c.863C>G; the sole germline observation is a single 1-star laboratory ClinVar submission without control comparison, and COSMIC counts are somatic-only.
PP4 not met: no proband phenotype or family-history documentation exists in the case bundle; the ClinVar condition label alone cannot establish a highly specific single-etiology phenotype.
PP5 not met: only an exact-variant ClinVar expert-panel (3-star) Pathogenic/Likely pathogenic classification can trigger PP5; this record has 0 expert-panel submissions (1-star ordinary laboratory assertion).
BP5 not met: no alternate genetic cause or phase data is documented.
BP6 not met: the sole ClinVar assertion is Pathogenic; no benign/likely-benign (expert-panel) classification exists.
Net contribution of this group: no pathogenic-supporting evidence (PS4/PP4/PP5 all not met) and no benign-supporting evidence (BP5/BP6 both not met); phenotype/prevalence criteria contribute nothing to the final classification, which will be driven by other groups (e.g., PVS1 for this nonsense variant).
PM3: not_applicable - NF2-related schwannomatosis is autosomal dominant (PMID:19545378); PM3 is defined only for recessive disorders (PMID:25741868).
BP2: not_assessed - no phase information exists for c.863C>G; no observation in trans with a pathogenic variant (dominant disease) or in cis with a pathogenic variant is documented in ClinVar or any retrieved publication.
Governing framework: no ClinGen CSPEC, VCEP materials, or NF2-specific PP3/BP4 lookup spreadsheet were found (vcep_materials.json empty; cspec found: false; final_classification_framework = generic_acmg_fallback, precedence_rank 3). Generic ACMG/AMP 2015 (PMID:25741868) therefore governs this group.
Variant class: NM_000268.3:c.863C>G is a nonsense variant (NP_000259.1:p.(Ser288Ter), exon 9, canonical_splice_consensus: false). The truncating effect is a direct sequence-level consequence adjudicated under PVS1 by the PVS1 group; PP3/BP4 are computational-prediction criteria that must not be stacked on (PP3) or used to negate (BP4) an established null consequence.
Splice path (SpliceAI): max delta score = 0.00 with all four delta scores (DS_AG/AL/DG/DL) = 0.0; variant_consequence = sequence_variant. No splice impact predicted, so the splice path provides no PP3 support and cannot support BP4 by itself (BP4 requires multiple lines of evidence and an overall no-impact conclusion, which is false for a truncating variant).
Missense path (BayesDel/REVEL): BayesDel noAF score 0.66 was computed but is a missense-calibrated prediction and is not applicable to a nonsense allele; REVEL lookup failed (found: false, score null). Neither predictor is usable for PP3/BP4 adjudication on this variant.
BP7 (synonymous-variant criterion) is outside this group's assigned criteria list and inapplicable here because the variant is not synonymous.
No publication in the case bundle mentions the exact variant (c.863C>G / p.Ser288Ter / S288*); therefore no literature is cited for PP3/BP4, consistent with the strict variant-grounding rule.
Framework: no ClinGen CSPEC and no VCEP specification exists for NF2 (cspec.found=false, gene_vcep_dir=null, precedence_rank=3), so generic ACMG/AMP 2015 (PMID:25741868) governs the population criteria, with pipeline non-VCEP frequency conventions (BA1>1%, BS1>0.3%, PM2<0.1% or absent).
Core population fact: NM_000268.3:c.863C>G (p.Ser288Ter) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (AF = 0 across all queried datasets).
BA1 not met: AF 0 is far below the 5% stand-alone threshold (and below the 1% pipeline threshold).
BS1 not met: AF 0 is below any frequency 'greater than expected' for NF2-related schwannomatosis (prevalence ~1:60,000 per PMID:19545378; expected carrier AF ~1e-5) and below the 0.3% pipeline threshold.
BS2 not met: no healthy adult heterozygotes (or any carriers) observed in population cohorts; the sole germline record is a single Pathogenic clinical submission in an affected context and is not usable as a healthy-adult observation.
PM2 met (supporting): absence from three large multi-ethnic cohorts (>1,000 individuals each) supports rarity; consistent with a nonsense variant in a LoF-constrained disease gene.
Threshold artifacts: somatic COSMIC count (n=10) is tumor-derived and was excluded from all germline population criteria; ClinVar's Pathogenic final classification was not used to infer any population criterion.
Net population-group contribution: PM2 (supporting, pathogenic direction); BA1/BS1/BS2 not met.
No criteria match.
NM_000268.3:c.863C>G is a nonsense (null) variant creating a premature stop codon at codon 288 of NP_000259.1 (p.Ser288Ter) in NF2, located in exon 9 of 16 exons. (1) Loss of function is an established germline disease mechanism for NF2 (NF2-related schwannomatosis, tumor suppressor gene; pvs1_gene_context reports lof_mechanism_supported=true and pvs1_gene_gate='eligible'; PMID:9643284 demonstrates truncating NF2 mutations cause severe NF2, PMID:19545378 states the majority of NF2 pathogenic mutations are truncating, leading to a non-functional protein). (2) Variant class is nonsense, the prototype null variant under the ClinGen SVI PVS1 recommendations (pvs1_generic_framework, PMC6185798). (3) NMD is predicted: exon 9 is neither the last exon (exon 16) nor within the last 50 bp of the penultimate exon; the predicted protein is truncated to 288 of 595 amino acids, removing the C-terminal ~52% of merlin including the remainder of the FERM domain and the entire alpha-helical and C-terminal ERM domains. (4) No downgrade for population LoF enrichment: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, and exon 9 is not a known LoF-tolerant region. (5) Transcript relevance: NM_000268.3 (NP_000259.1, transcript variant 1) is the principal RefSeq NF2 transcript and the transcript used by ClinVar for this variant (ClinVar title NM_000268.4:c.863C>G p.Ser288Ter); SpliceAI max delta = 0.00 excludes a competing splice effect, so the sole consequence is the premature termination. All PVS1 conditions of the generic framework are satisfied; PVS1 is applied at full Very Strong strength. No downgrade considerations apply (no NMD escape, no distal/terminal exon location, no population LoF enrichment in the exon). ClinVar's Pathogenic submission was NOT used as PVS1 evidence.
pvs1_generic_framework (ClinGen SVI PVS1 recommendations, PMC6185798) applied under generic ACMG/AMP 2015 (PMID:25741868): PVS1 = null variant (nonsense) in a gene where LoF is a known mechanism of disease, in an NMD-expected position (not last exon / not last 50 bp of penultimate exon), with no population LoF enrichment in the affected exon and a biologically relevant transcript -> full Very Strong PVS1.
PM2 is met: the variant is absent from three large, multi-ethnic general-population cohorts - gnomAD v2.1 exomes (GRCh37 22-30061031-C-G, search_status='absent'), gnomAD v4.1 (GRCh38 chr22-29665042-C-G, search_status='absent'), and gnomAD-Canada v1.0 (search_status='absent') - each far exceeding the ACMG/AMP 2015 minimum of >1,000 individuals, and the variant is a predicted loss-of-function nonsense change (p.Ser288Ter) in NF2, a gene with established germline LoF disease mechanism (pvs1_gene_context: lof_mechanism_supported=true), making absence in population databases highly informative. Strength: the generic ACMG/AMP 2015 framework labels PM2 as moderate, but ClinGen SVI recalibration and this pipeline's non-VCEP convention apply PM2 at supporting strength; supporting is used here for consistency. Somatic COSMIC occurrences (COSV58523216, n=10) are somatic tumor data and were NOT used as germline population evidence.
ACMG/AMP 2015 (PMID:25741868): 'If a variant is absent from (or below the expected carrier frequency if recessive) a large general population or a control cohort (>1,000 individuals) and the population is race-matched... this observation can be considered a moderate piece of evidence for pathogenicity (PM2)'; pipeline non-VCEP PM2 threshold AF <0.1% (absent qualifies).
PS4 requires the prevalence of the variant in affected individuals to be significantly increased compared with controls (OR > 5.0 with CI excluding 1.0, or, for very rare variants, prior observation in multiple unrelated patients with the same phenotype plus absence in controls). No case-control or cohort prevalence study exists for NM_000268.3:c.863C>G (p.Ser288Ter) anywhere in the case evidence bundle. The only germline affected-individuals observation is a single 1-star ClinVar clinical-laboratory submission (SCV001190519, FRIGE's Institute of Human Genetics, Pathogenic, no controls, no statistical comparison) - insufficient even for the PS4 Note 2 moderate tier, which requires multiple unrelated affected patients. COSMIC (COSV58523216, n=10) reflects somatic tumor observations only and is not germline case-control evidence. A full-text/abstract screen of all retrieved NF2 literature (PMID:19545378, PMID:9643284, PMID:8755919, PMID:22825583, PMID:20301380, PMID:32602153, PMID:25356965) found zero occurrences of the exact variant (c.863 / p.Ser288Ter), so no publication provides variant-level prevalence data. PS4 is therefore not met. Governing framework: generic ACMG/AMP 2015 (no NF2 CSPEC/VCEP exists; cspec.found=false, framework_mode=generic_acmg).
PS4 (Richards et al. 2015, PMID:25741868): prevalence of the variant in affected individuals significantly increased vs controls (OR>5.0, CI excluding 1.0; or Note 2: multiple unrelated affected patients with same phenotype and absence in controls, moderate)
PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology, and the 2015 guidance stresses that a phenotype merely matching the gene's known spectrum is not evidence (testing sensitivity must be high, the syndrome well-defined with little overlap, the gene free of substantial benign variation, and family history consistent with the mode of inheritance). The case bundle contains no proband phenotype or family-history documentation whatsoever. The only phenotype-adjacent datum is the condition label 'Neurofibromatosis, type 2' on the single ClinVar submission (api_conditions), which records the testing indication, not a verified proband phenotype, and cannot by itself establish the 'highly specific phenotype' requirement of PP4. Per the governing instruction, a criterion must not be inferred from another source's final classification, and the Pathogenic label on the submission cannot substitute for phenotype evidence. PP4 is therefore not met on the available evidence; it would become assessable only if proband phenotype/family-history data (e.g., bilateral vestibular schwannomas) were supplied for human review.
PP4 (Richards et al. 2015, PMID:25741868): patient's phenotype or family history is highly specific for a disease with a single genetic etiology (supporting)
Per the governing pipeline rule for this group, PP5 applies ONLY for an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger PP5. The ClinVar record VCV000870602 contains exactly one submission (SCV001190519, Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics): classification Pathogenic, review status 'criteria provided, single submitter' (1 star), germline clinical testing. The submission audit explicitly records expert_panel_submissions=0 and is_expert_panel=false. This is an ordinary clinical-laboratory assertion, not an expert-panel classification, so PP5 is not met. (Note: the generic 2015 ACMG/AMP PP5 text would permit reputable-laboratory assertions as supporting evidence, but the governing instruction for this pipeline supersedes that and restricts PP5 to expert-panel classifications.)
PP5 per governing pipeline rule: exact-variant ClinVar expert-panel (3-star) classification Pathogenic/Likely pathogenic supports PP5 (supporting); ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger (base text: Richards et al. 2015, PMID:25741868)
BA1 (stand-alone benign) requires an allele frequency high enough that the variant is effectively impossible for the disorder (ACMG/AMP 2015: AF >5% in a general population database). This variant, NM_000268.3:c.863C>G (p.Ser288Ter) in NF2, is ABSENT from gnomAD v2.1 (GRCh37 22-30061031-C-G), gnomAD v4.1 (GRCh38 chr22-29665042-C-G), and gnomAD-Canada v1.0 (search_status='absent', found=false in evidence.json for all three). AF = 0 is far below any BA1 threshold (5% generic; pipeline non-VCEP threshold 1%), so BA1 is definitively not met.
ACMG/AMP 2015 (PMID:25741868): 'if over 5%, it is considered as stand-alone support (BA1)' - allele frequency in a control population >5% (dominant disorder) qualifies as stand-alone benign; pipeline non-VCEP convention uses >1%.
BS1 (strong benign) requires an allele frequency greater than expected for the disorder (ACMG/AMP 2015, Table 6). NF2-related schwannomatosis has a prevalence of roughly 1:60,000 (PMID:19545378), implying a maximum credible germline allele frequency on the order of ~1e-5; the pipeline non-VCEP BS1 threshold is AF >0.3%. The variant has AF = 0 (absent from gnomAD v2.1, v4.1, and gnomAD-Canada), so it does not approach any BS1 threshold in any ancestry subpopulation. Not met with high confidence.
ACMG/AMP 2015 (PMID:25741868): 'an allele frequency in a control population that is greater than expected for the disorder (Table 6) is considered strong support for a benign interpretation for a rare Mendelian disorder (BS1)'; pipeline non-VCEP convention BS1 >0.3%.
BS2 (strong benign) requires the variant to be observed in a well-documented healthy adult - heterozygous for an autosomal dominant disorder with full penetrance expected at an early age (ACMG/AMP 2015). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, i.e., no heterozygous (or any) observations in large population cohorts; no homozygotes reported. The only germline observation (ClinVar VCV000870602, SCV001190519) is a single Pathogenic clinical-testing submission in an affected context and cannot serve as a healthy-adult observation, and final classifications from other sources must not be used to infer criteria. BS2 not met.
ACMG/AMP 2015 (PMID:25741868): 'if the disease under investigation is fully penetrant at an early age and the variant is observed in a well-documented healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) condition, then this is considered strong evidence for a benign interpretation (BS2)'.
BP5 (Richards et al. 2015) applies when the variant is observed in a case with a clear alternate genetic cause of disease, giving supporting evidence for benignity (stronger for dominant-disorder genes). No alternative-locus explanation is documented anywhere in the case bundle: there is no report of a second pathogenic variant in another gene, no trans/cis phase data, and no alternative genetic etiology for the proband. The sole ClinVar submission attributes the variant to Neurofibromatosis, type 2 without any alternate-cause finding. With no evidence of an alternate molecular basis, BP5 cannot be met.
BP5 (Richards et al. 2015, PMID:25741868): variant observed in a case with a clear alternate genetic cause of disease - supporting evidence for benign classification
Per the governing pipeline rule for this group, BP6 applies ONLY for an exact-variant ClinVar expert-panel classification of Benign/Likely benign; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger BP6. The ClinVar record VCV000870602 is classified Pathogenic (sole submission SCV001190519, 1 star, ordinary clinical laboratory, expert_panel_submissions=0) - there is no benign or likely-benign assertion of any kind, from any submitter, expert panel or otherwise. BP6 is therefore not met.
BP6 per governing pipeline rule: exact-variant ClinVar expert-panel (3-star) classification Benign/Likely benign supports BP6 (supporting); non-expert assertions never trigger (base text: Richards et al. 2015, PMID:25741868)
PS2 (Richards et al. 2015, PMID:25741868) requires a de novo occurrence of the variant in a proband with a consistent phenotype, with maternity and paternity confirmed. No proband clinical description, no parental genotype results, and no de novo report for NM_000268.3:c.863C>G (p.Ser288Ter) are present anywhere in the case evidence. The single ClinVar germline submission (SCV001190519, FRIGE's Institute of Human Genetics) classifies the variant Pathogenic but provides no criteria and no de novo or parental-testing data; a classification alone cannot establish PS2. Evidence is insufficient, so PS2 is not assessed.
generic_acmg_2015: PS2 de novo with confirmed parental genotypes
PS3 (ACMG/AMP 2015, PMID:25741868) requires well-established in vitro or in vivo functional studies demonstrating a deleterious effect on the gene or gene product, with strength calibrated to assay validation (default Strong). No variant-specific functional assay exists for NM_000268.3:c.863C>G (NP_000259.1:p.Ser288Ter) anywhere in the evidence bundle: (1) full-text search for 'c.863C>G', 'c.863', 'Ser288', 'S288', 'codon 288', '288X' returned zero matches across all six available full texts (publications/19545378.txt, 22825583.txt, 9643284.txt, 25741868.txt, 25356965.txt, 32602153.txt), and the 9643284 truncating-mutation list contains no codon-288 change; (2) OncoKB curates a variant-specific biological-effect label of 'Likely Loss-of-function' and oncogenicity 'Likely Oncogenic' for NF2 S288* (is_variant_specific=true), but this is a curated inference from the truncating alteration plus gene-level literature, not a validated assay with controls, and the 'Likely' qualifier marks it as inferred; (3) COSMIC records somatic recurrence of this exact variant (COSV58523216, n=10), which is observational tumor-sequencing data, not a functional study; (4) the functional-theme papers (PMID:9643284, 19545378, 22825583, 8755919) provide gene-level loss-of-function mechanism context for the truncating class but never mention this variant. Per strict citation grounding, gene-level discussion cannot be cited as variant-specific PS3 evidence. Additionally, the truncating consequence of this nonsense allele is already accounted for under PVS1 (separate consequence/loss-of-function group); applying PS3 for the same predicted loss-of-function effect would double-count the same functional consequence. PS3 therefore cannot be assessed: evidence is insufficient, and strength cannot be calibrated in the absence of a validated variant-specific assay.
ACMG/AMP 2015 PS3 (Richards et al., PMID:25741868): well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product; default strength Strong, requiring validated assays reflecting the biological environment. Generic ACMG fallback applied (no NF2 VCEP/CSPEC; final_classification_framework found=false, precedence_rank 3, framework_mode generic_acmg). Status: not_assessed - no variant-specific validated functional study available.
PM6 (Richards et al. 2015, PMID:25741868) requires an assumed de novo occurrence without confirmation of parental identity. No de novo report for NM_000268.3:c.863C>G exists in the case evidence, and no parental testing data are available to support an unconfirmed de novo scenario. Germline origin noted in the ClinVar submission does not by itself establish a de novo event. Evidence is insufficient, so PM6 is not assessed.
generic_acmg_2015: PM6 assumed de novo (parental identity unconfirmed)
PP1 (Richards et al. 2015, PMID:25741868) requires co-segregation of the variant with disease in multiple affected family members in a gene definitively known to cause the disease. No segregation data for NM_000268.3:c.863C>G are present in the case bundle: there are no affected-family-member genotypes, no meiosis counts, and no segregation analyses in any reviewed publication. Evidence is insufficient, so PP1 is not assessed.
generic_acmg_2015: PP1 co-segregation in multiple affected family members
BS3 (ACMG/AMP 2015, PMID:25741868) requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing, with strength calibrated to assay validation (default Strong). No functional study demonstrating preserved protein function or splicing exists for NM_000268.3:c.863C>G (p.Ser288Ter) in the evidence bundle; full-text searches for the variant across all six available publications returned zero mentions, and no mRNA/cDNA-level analysis, minigene assay, or merlin activity/complementation assay showing wild-type-equivalent function was retrieved. SpliceAI predicts no splice impact (max delta score 0.00), but this is an in silico prediction, not a well-established functional study, and it is moot for this nonsense allele because the protein is already truncated at residue 288 of 596 (deleting the C-terminal half, including the alpha-helical and C-terminal domains); absence of a splice alteration does not demonstrate preservation of protein function. All directional evidence points to a damaging effect rather than absence of damage (nonsense consequence p.Ser288Ter; OncoKB curated 'Likely Loss-of-function' for this exact variant; COSMIC somatic recurrence n=10; gene-level association of NF2 truncating mutations with earlier onset and more severe disease in PMID:9643284). Evidence is therefore insufficient to assess BS3: the criterion is not met on available evidence and remains not_assessed pending validated functional data demonstrating wild-type-equivalent function. Adjudicated under generic ACMG/AMP 2015 because no ClinGen CSPEC/VCEP specification for NF2 exists.
ACMG/AMP 2015 BS3 (Richards et al., PMID:25741868): well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing; default strength Strong. Generic ACMG fallback applied (no NF2 VCEP/CSPEC; final_classification_framework found=false, precedence_rank 3, framework_mode generic_acmg). Status: not_assessed - no functional studies available; in silico predictors do not qualify.
BS4 (Richards et al. 2015, PMID:25741868) requires lack of segregation of the variant in affected family members (i.e., a variant present in an affected individual who does not carry the variant, or in an unaffected carrier relative, contradicting co-segregation). No family genotype data exist for NM_000268.3:c.863C>G, so absence of segregation cannot be established. Evidence is insufficient to conclude BS4 is met; the criterion is not assessed.
generic_acmg_2015: BS4 lack of segregation in affected family members
BP2 (ACMG/AMP 2015, PMID:25741868) requires observing the variant in trans with a pathogenic variant in a fully dominant disease, or in cis with a pathogenic variant in any inheritance pattern; phase determination normally requires parental testing or family segregation ('Testing parental samples to determine whether the variant occurs in cis ... or in trans ...'). The evidence bundle contains no phasing information: ClinVar VCV000870602 has a single germline submission (SCV001190519, FRIGE Institute of Human Genetics, Pathogenic, criteria provided/single submitter) with no family or allele-configuration data; its only validated PMID (25741868) is the ACMG framework paper itself and carries no variant-specific case evidence. No publication in the case corpus mentions c.863C>G / p.Ser288Ter (0/6 full-text files matched), so no proband/family observation of trans or cis configuration with a pathogenic variant is documented. gnomAD v2.1/v4.1/Canada absence provides population rarity but no phase information. Evidence is therefore insufficient to evaluate BP2; the criterion is not met on any data, but formally not_assessed pending phase/family data.
BP2 (ACMG/AMP 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.' Main text: 'In the context of dominant disorders the detection of a variant in trans with a pathogenic variant can be considered supporting evidence for a benign impact (BP2).' Requires documented allele phase.
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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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 is defined for recessive disorders: 'For recessive disorders, detected in trans with a pathogenic variant' (Richards et al. 2015, PMID:25741868). The disease associated with NF2, NF2-related schwannomatosis (neurofibromatosis type 2), is autosomal dominant (PMID:19545378: 'autosomal dominant disease with usually a 50% risk of transmission from an affected individual to their offspring'), and the variant is in a dominant-disease gene. The criterion's core premise (recessive inheritance) does not hold for this gene/disease, so PM3 is not applicable regardless of any allele-phase data. No VCEP/CSPEC specification for NF2 exists in this case (framework_mode: generic_acmg), so the generic ACMG/AMP 2015 rule governs. For completeness, the case bundle contains no observation of this variant in trans with a pathogenic variant, which independently means PM3 could not be met even under a recessive model.
PM3 (ACMG/AMP 2015, PMID:25741868): 'For recessive disorders, detected in trans with a pathogenic variant.' Applies only to recessive disease genes; 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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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
Variant NM_000268.3:c.863C>G is a nonsense change (NP_000259.1:p.(Ser288Ter), exon 9, non-canonical splice position). PP3 is a computational-evidence criterion intended for variants whose effect requires prediction (missense, in-frame indels, splice-region changes). For a nonsense allele the truncating consequence is established directly from the sequence and is adjudicated under PVS1 by the PVS1 group; applying PP3 on top of PVS1 for the same truncation would double-count the same effect. Splice path: SpliceAI max delta = 0.00 (DS_AG/AL/DG/DL all 0.0) predicts no splice impact, so the splice path does not support PP3. Missense path: BayesDel score 0.66 is a missense-calibrated prediction and is not applicable to a nonsense allele; REVEL lookup returned no score (found: false). No NF2-specific VCEP/CSPEC PP3/BP4 specification or pre-assigned lookup exists (framework_mode: generic_acmg, precedence_rank 3), so the generic ACMG/AMP 2015 scope applies. PP3 therefore not applicable; no computational evidence is available or appropriate to meet it.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) - generic ACMG/AMP 2015 (Richards et al., PMID:25741868). Not applicable to variants with established null/truncating consequence (PVS1 domain) to avoid double-counting.
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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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
BP4 requires multiple lines of computational evidence suggesting NO impact on the gene or gene product. This variant is a nonsense change (p.Ser288Ter) that definitively impacts the gene product via premature termination; the single available observation that SpliceAI predicts no splice effect (max delta = 0.00) addresses only the splice path and cannot constitute evidence of no overall impact on gene/gene product. Applying BP4 would contradict the established truncating consequence (adjudicated under PVS1). Additionally, BP4 requires multiple independent lines of evidence: only SpliceAI is available (REVEL not found; BayesDel 0.66 is missense-calibrated and inapplicable to a nonsense allele). No NF2-specific VCEP/CSPEC specification exists (generic ACMG/AMP 2015 fallback), and no pre-assigned BP4 lookup applies. BP4 therefore not applicable to this variant class.
BP4: Multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.) - generic ACMG/AMP 2015 (Richards et al., PMID:25741868). Not applicable to variants with established null/truncating consequence (PVS1 domain).
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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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.
Variant NM_000268.3:c.863C>G is a nonsense change (NP_000259.1:p.(Ser288Ter), exon 9, non-canonical splice position). PP3 is a computational-evidence criterion intended for variants whose effect requires prediction (missense, in-frame indels, splice-region changes). For a nonsense allele the truncating consequence is established directly from the sequence and is adjudicated under PVS1 by the PVS1 group; applying PP3 on top of PVS1 for the same truncation would double-count the same effect. Splice path: SpliceAI max delta = 0.00 (DS_AG/AL/DG/DL all 0.0) predicts no splice impact, so the splice path does not support PP3. Missense path: BayesDel score 0.66 is a missense-calibrated prediction and is not applicable to a nonsense allele; REVEL lookup returned no score (found: false). No NF2-specific VCEP/CSPEC PP3/BP4 specification or pre-assigned lookup exists (framework_mode: generic_acmg, precedence_rank 3), so the generic ACMG/AMP 2015 scope applies. PP3 therefore not applicable; no computational evidence is available or appropriate to meet it.
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) - generic ACMG/AMP 2015 (Richards et al., PMID:25741868). Not applicable to variants with established null/truncating consequence (PVS1 domain) to avoid double-counting.
BP4 requires multiple lines of computational evidence suggesting NO impact on the gene or gene product. This variant is a nonsense change (p.Ser288Ter) that definitively impacts the gene product via premature termination; the single available observation that SpliceAI predicts no splice effect (max delta = 0.00) addresses only the splice path and cannot constitute evidence of no overall impact on gene/gene product. Applying BP4 would contradict the established truncating consequence (adjudicated under PVS1). Additionally, BP4 requires multiple independent lines of evidence: only SpliceAI is available (REVEL not found; BayesDel 0.66 is missense-calibrated and inapplicable to a nonsense allele). No NF2-specific VCEP/CSPEC specification exists (generic ACMG/AMP 2015 fallback), and no pre-assigned BP4 lookup applies. BP4 therefore not applicable to this variant class.
BP4: Multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.) - generic ACMG/AMP 2015 (Richards et al., PMID:25741868). Not applicable to variants with established null/truncating consequence (PVS1 domain).
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.863C>G in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Ser288Ter). 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 = 0.00). BayesDel score = 0.66.
8 paper records listed. 3 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The majority of these mutations were truncating mutations, leading to a smaller and probably non-functional protein product.
Location Review section 'Constitutional mutations' (mutation spectrum paragraph); see also 'Nonsense 16 (15%) 67 (35%) 28 (37%) 111 (22%)' mutation-spectrum table row
Context Narrative clinical/molecular review of NF2 combining epidemiological and mutation-spectrum data from the literature (includes mutation-class frequency tables).
PS3 Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product ... BS3 Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
Location Evidence criteria definitions (pathogenic and benign evidence categories, Table 4), Richards et al. 2015 (publications/25741868.txt)
Context ACMG/AMP joint consensus recommendations for sequence variant interpretation; framework source for this case (generic ACMG fallback, PMID:25741868)
Subjects with truncating mutations were significantly more likely to have symptoms before 20 years of age (p<0.001) and to develop at least two symptomatic CNS tumours in addition to vestibular schwannoma before 30 years (p<0.001).
Location Abstract; Results section (mutation classes listed in Results, '22 nonsense mutations...three frameshift insertions, five missense mutations, six splice site mutations')
Context Cohort study: mutation analysis of blood samples from 125 unrelated NF2 families (plus 17 modified-criteria families); phenotypic severity compared across truncating vs non-truncating mutation classes.
About 35-40% of MPMs carry inactivating mutations at the neurofibromatosis 2 ( NF2) locus, which encodes for the FERM domain protein Merlin.
Full text, section 'NF2 Loss and mTOR Blockade' (publications/22825583.txt)
The gene predisposing to neurofibromatosis type 2 (NF2) on human chromosome 22 has revealed a wide variety of different mutations in NF2 individuals.
Abstract (PubMed), via literature_pass.json high_priority_papers snippet; no full text in this case (publications/8755919.png only)
"NF2-Related Schwannomatosis." (GeneReviews chapter; pubdate 1993; authors Adam MP, Bick S, Mirzaa GM)
source_registry.json PMID:20301380 and literature_pass.json high_priority_papers entry (abstract empty, full text not retrieved; no fulltext_map.json entry)
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 has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 870602)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58523216, n = 10 times).
This variant does not lie in a statistically significant hotspot.