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: the p.Gln320Ter premature stop codon lies ~780 nucleotides upstream of the final exon-exon junction, well beyond the ~50-nucleotide threshold for nonsense-mediated decay.
Met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
Met: SpliceAI max delta 0.003 is far below the ~0.2 splice-altering threshold, predicting no splice impact.
VUS: with no NF2-specific VCEP, generic ACMG/AMP 2015 rules applied - PVS1 (very strong) plus PM2 (supporting) would reach likely pathogenic, but conflicting BP4 (supporting) benign evidence holds the result at VUS.
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: 0.003. 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; COSV58522975, n = 4 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: 3 met · 5 not met · 11 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 applied at very strong strength: NM_000268.3:c.958C>T (p.Gln320Ter) is a nonsense variant in exon 10 of 16, far upstream of the final exon-exon junction, predicted to trigger NMD; NF2 loss of function is an established germline disease mechanism; no NF2 VCEP-specific PVS1 modifications exist, so the generic ClinGen SVI PVS1 framework (PMC6185798) applies without downgrade.
No applicable NF2-specific VCEP or gene-specific framework was present in the case bundle, so generic ACMG/AMP definitions were used.
The available bundle lacks case-level proband, parental-testing, pedigree, meiosis, segregation, and non-segregation data for the exact variant.
All four requested criteria are therefore not_assessed; no other criteria were adjudicated.
Bundle contains no functional/experimental assay evidence (splicing, protein stability, complementation, NMD, or cell-based studies) for this exact variant; therefore PS3 and BS3 are both not_assessed rather than met or not_met.
No NF2 ClinGen VCEP specification is present in the case (cspec.found=false, gene_vcep_dir=null), so generic ACMG PS3/BS3 assay-validity requirements were the applicable standard but could not be met due to absence of any assay data.
No NF2-specific ClinGen VCEP/CSPEC PP3/BP4 lookup materials were found for this case (vcep_materials.json: cspec.found=false, gene_vcep_dir=null); generic ACMG/AMP fallback logic was applied.
This variant, NM_000268.3:c.958C>T (p.Gln320Ter), is a nonsense change, so the missense computational sub-path (REVEL/BayesDel) is not the primary applicable mechanism; REVEL is unavailable and BayesDel (0.66) has no verified published calibration threshold in this pipeline and was excluded from PP3/BP4 use.
SpliceAI predicts no splice impact (max delta score = 0.003), which is used on the splice-impact sub-path to support BP4 (supporting) and to refute PP3.
No criteria match.
NM_000268.3:c.958C>T produces NP_000259.1:p.(Gln320Ter), a premature stop codon in exon 10 of 16 coding exons of NF2 (CCDS13861.1; c.958 falls within the c.886-999 exon-10 boundary per VariantValidator exon map). The final coding exon spans c.1738 to the 3' UTR (*3798); the penultimate exon-exon junction lies at c.1737/1738. Because the PTC at c.958 (~780 nt upstream of the last exon-exon junction) is far more than the ~50 nt threshold from the final exon-exon junction, the transcript is predicted to undergo nonsense-mediated decay (NMD) under the ClinGen SVI PVS1 decision tree (PMC6185798). The truncation, if translated, would remove residues 320-596 (277 of 596 aa, ~46% of the protein), eliminating the C-terminal FERM-C interacting/actin-binding region and coiled-coil domain of merlin. Germline NF2 loss-of-function is an established disease mechanism for NF2-related schwannomatosis (pvs1_gene_context: lof_mechanism_supported=true, germline disease-focused literature identified, gene loss-of-function-intolerant). No CSPEC/VCEP-specific PVS1 rule was found for NF2 (framework_mode=generic_acmg, cspec.found=false), so the generic ACMG/ClinGen SVI PVS1 framework was applied per case fallback policy. No evidence in the bundle indicates the affected exon is subject to biologically relevant alternative splicing/exon skipping, is enriched for population loss-of-function variation, or that this class of variant escapes NMD in NF2; SpliceAI predicts no splice disruption (max delta 0.003), consistent with a straightforward nonsense/NMD-triggering outcome rather than a splice-altering effect. No repeat-region or low-complexity-region caveat applies to this single-nucleotide nonsense substitution. PVS1 is therefore met at very strong strength.
PVS1 (ClinGen SVI PVS1 decision tree, PMC6185798): nonsense variant predicted to trigger NMD in a gene with an established germline loss-of-function disease mechanism, no VCEP-specific gene modification available.
NM_000268.3:c.958C>T (NF2 p.Gln320Ter) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. NF2-related schwannomatosis is a rare dominantly inherited tumor-predisposition disorder, with a reported prevalence around 1 in 60,000. The observed absence across population datasets supports PM2 at supporting strength under the generic ACMG/AMP framework; no homozygote or ancestry-specific frequency artifact was identified.
Generic ACMG/AMP PM2: absent from, or extremely rare in, population databases appropriate to the disease context; applied here at supporting strength because the exact variant is absent from multiple population datasets.
SpliceAI predicts no significant splice impact for NM_000268.3:c.958C>T (max delta score = 0.003 across all four donor/acceptor gain/loss scores), consistent with a benign computational prediction on the splice-impact path. This is well below the commonly used SpliceAI splice-altering threshold of ~0.2 established in the original SpliceAI calibration study (Jaganathan et al. 2019, PMID 30661751). No NF2 VCEP/CSPEC-specific PP3/BP4 lookup was found in vcep_materials.json to override or supersede this generic-ACMG application. The missense in-silico sub-path (REVEL/BayesDel) is not applicable as this is a nonsense variant, and in any case BayesDel lacks a verified published threshold in this pipeline, so BP4 here rests solely on the splice-impact evidence.
generic_acmg_fallback (no NF2 VCEP-specific PP3/BP4 lookup found)
NM_000268.3:c.958C>T is a nonsense change (NP_000259.1:p.(Gln320Ter)), not a missense or splice-region substitution. No governing NF2 VCEP/CSPEC materials or gene-specific PP3/BP4 lookup were found for this case (vcep_materials.json: cspec.found=false, no gene_vcep_dir, generic_acmg fallback), so generic ACMG guidance applies. On the missense in-silico sub-path, REVEL is not available for this variant (revel.found=false) and BayesDel, while scored (0.66), has no verified published calibration threshold available to this pipeline, so it must be treated as not_available for PP3/BP4 per this pipeline's calibration policy regardless of the numeric value. On the splice-impact sub-path, SpliceAI predicts no meaningful splice disruption (max delta score = 0.003; DS_AG=0.001, DS_AL=0.001, DS_DG=0.0, DS_DL=0.003), which does not meet any reasonable splice-altering threshold, so this cannot support PP3. No computational evidence in this bundle supports a damaging effect, so PP3 is not met.
generic_acmg_fallback (no NF2 VCEP-specific PP3/BP4 lookup found)
PP5 is not applicable under the requested rule because the exact-match ClinVar record has no expert-panel submission. The available classifications are from OMIM without assertion criteria and a single clinical laboratory submission; neither an ordinary laboratory submission nor an aggregate ClinVar Pathogenic label can trigger PP5.
PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; non-expert, single-laboratory, ordinary-submission, and aggregate labels do not qualify.
No population allele frequency meeting a stand-alone benign threshold is reported for NM_000268.3:c.958C>T. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore BA1 is not met.
Generic ACMG/AMP BA1: stand-alone benign evidence requires an allele frequency high enough to establish that the variant is too common for the disorder; no such frequency is present here.
No population frequency above the disease-specific maximum credible allele frequency is reported for NM_000268.3:c.958C>T. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore BS1 is not met.
Generic ACMG/AMP BS1: allele frequency greater than expected for the disorder can support benign evidence; an above-threshold frequency is not observed here.
BP6 is not applicable under the requested rule because no exact-variant ClinVar expert-panel classification of Benign or Likely benign exists. The available exact-match submissions are non-expert Pathogenic assertions, so they cannot trigger BP6.
BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign classification; non-expert, single-laboratory, ordinary-submission, and aggregate labels do not qualify.
No case-specific evidence documents that NM_000268.3:c.958C>T was absent from both tested parents, nor are validated trio testing results, parental relationships, or a de novo observation in the proband provided. The exact-variant literature trail does not supply auditable parental-testing details in the consolidated bundle. PS2 therefore cannot be applied.
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; apply only when the de novo observation is adequately documented.
No functional/experimental assay data (e.g., in vitro splicing, protein stability, NMD, complementation, or reporter assays) for NM_000268.3:c.958C>T (p.Gln320Ter) were found anywhere in the case-evidence bundle. No ClinGen NF2 VCEP specification was located (cspec.found=false, gene_vcep_dir=null), so no gene-specific PS3 calibration is available either. OncoKB and COSMIC entries describe curated somatic oncogenicity annotation and tumor-registry counts, not a validated functional assay of variant effect, and are not appropriate PS3 evidence. No high-priority literature papers in the bundle are tagged with a functional theme testing this specific variant.
The exact variant is linked in ClinVar to a single-submitter laboratory assertion stating that it was observed in multiple individuals with histories consistent with NF2-related disease. However, no independent case series, case count, control comparison, enrichment statistic, or sufficiently detailed phenotype data are available in the reviewed evidence to establish the ACMG/AMP PS4 requirement that the prevalence in affected individuals be significantly increased compared with controls.
Generic ACMG/AMP PS4 framework used because no NF2-specific VCEP/CSPEC specification was retrieved; apply only with significant enrichment of the exact variant in affected individuals versus controls.
No case-specific evidence indicates that NM_000268.3:c.958C>T was assumed to be de novo without parental confirmation. There is no documented proband phenotype plus unconfirmed de novo observation sufficient for PM6.
Generic ACMG/AMP PM6: assumed de novo, without confirmation of paternity and maternity, in a patient with the disease and no family history; apply only when the case documentation supports the assumption.
No affected relatives carrying NM_000268.3:c.958C>T, no number of informative meioses, and no family-specific segregation table or pedigree are provided. Phenotype consistency in relatives cannot be evaluated, so PP1 is not assessable.
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength depends on the number and informativeness of meioses and the phenotype fit.
No patient-specific clinical phenotype or diagnostic presentation for the exact variant is provided. General descriptions of NF2 and its diagnostic features do not establish that this patient's phenotype is highly specific for NF2.
Generic ACMG/AMP PP4 framework used because no NF2-specific VCEP/CSPEC specification was retrieved; requires a phenotype or highly specific clinical finding consistent with the relevant disease.
No evidence was provided that the variant occurs in healthy adults, in homozygous state, or in unaffected individuals at an age and ascertainment level that would support BS2. Population-database absence does not evaluate the BS2 unaffected-carrier or homozygote requirement.
Generic ACMG/AMP BS2: observation of the variant in healthy adults, including homozygotes where applicable, can support benign evidence; the required observations are unavailable.
No functional/experimental assay data showing normal/wild-type-like activity for NM_000268.3:c.958C>T (p.Gln320Ter) were found in the case-evidence bundle. No ClinGen NF2 VCEP specification is available to calibrate BS3. No source in the bundle reports a functional assay result for this variant, consistent with expectations for a truncating nonsense variant unlikely to have been functionally tested for benign evidence.
No informative unaffected relatives tested for NM_000268.3:c.958C>T are reported, and there is no family pedigree, age-related penetrance assessment, or non-segregation analysis. BS4 cannot be applied.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; apply only when informative family testing and phenotype assessment show that the variant does not track with disease.
BP2 requires observation of the assessed variant in trans with a pathogenic or likely pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder. NF2 is evaluated here as a dominant disorder, but the case-evidence bundle contains no second-variant finding, pathogenic/likely pathogenic partner, phase determination, or family-based allelic observation. BP2 cannot therefore be applied or excluded from the available evidence.
No reliable evidence shows that this variant is associated with a phenotype or disease mechanism inconsistent with the evaluated NF2-related condition. The available evidence is insufficient to assess BP5.
Generic ACMG/AMP BP5 framework used because no NF2-specific VCEP/CSPEC specification was retrieved; requires a variant observed in an individual with an alternative molecular basis for disease inconsistent with the evaluated condition.
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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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 a recessive-disease criterion requiring a pathogenic or likely pathogenic variant demonstrated in trans with the variant under assessment. The case is NF2-related disease, for which the available case context supports a germline autosomal-dominant tumor-predisposition disorder rather than a recessive inheritance model; therefore PM3 is not applicable. No PM3 evidence is used.
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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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.
SpliceAI predicts no significant splice impact for NM_000268.3:c.958C>T (max delta score = 0.003 across all four donor/acceptor gain/loss scores), consistent with a benign computational prediction on the splice-impact path. This is well below the commonly used SpliceAI splice-altering threshold of ~0.2 established in the original SpliceAI calibration study (Jaganathan et al. 2019, PMID 30661751). No NF2 VCEP/CSPEC-specific PP3/BP4 lookup was found in vcep_materials.json to override or supersede this generic-ACMG application. The missense in-silico sub-path (REVEL/BayesDel) is not applicable as this is a nonsense variant, and in any case BayesDel lacks a verified published threshold in this pipeline, so BP4 here rests solely on the splice-impact evidence.
generic_acmg_fallback (no NF2 VCEP-specific PP3/BP4 lookup found)
NM_000268.3:c.958C>T is a nonsense change (NP_000259.1:p.(Gln320Ter)), not a missense or splice-region substitution. No governing NF2 VCEP/CSPEC materials or gene-specific PP3/BP4 lookup were found for this case (vcep_materials.json: cspec.found=false, no gene_vcep_dir, generic_acmg fallback), so generic ACMG guidance applies. On the missense in-silico sub-path, REVEL is not available for this variant (revel.found=false) and BayesDel, while scored (0.66), has no verified published calibration threshold available to this pipeline, so it must be treated as not_available for PP3/BP4 per this pipeline's calibration policy regardless of the numeric value. On the splice-impact sub-path, SpliceAI predicts no meaningful splice disruption (max delta score = 0.003; DS_AG=0.001, DS_AL=0.001, DS_DG=0.0, DS_DL=0.003), which does not meet any reasonable splice-altering threshold, so this cannot support PP3. No computational evidence in this bundle supports a damaging effect, so PP3 is not met.
generic_acmg_fallback (no NF2 VCEP-specific PP3/BP4 lookup found)
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.958C>T in NF2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000259.1:p.(Gln320Ter). 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. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Disease prevalence has now risen to around 1 in 60,000
Location Epidemiology section
Context Narrative clinical and molecular review summarizing epidemiologic studies from North West England and Finland; not a variant-specific cohort study.
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 = 3291)
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; COSV58522975, n = 4 times).
This variant does not lie in a statistically significant hotspot.