Variant classification summary

NM_000268.3:c.778G>T

NF2 · NP_000259.1:p.(Glu260Ter) · NM_000268.3

GRCh37: chr22:30057296 G>T · GRCh38: chr22:29661307 G>T

Gene: NF2 Transcript: NM_000268.3

Final call

VUS

PVS1 very strong PM2 supporting BP4 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Glu260Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense variant p.(Glu260Ter) predicted to trigger nonsense-mediated decay, consistent with a null NF2 allele.

2

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.

3

BP4 (Supporting): SpliceAI max delta 0.149 below the ~0.2 cutoff predicts no significant splice disruption.

4

Final classification: VUS - the combination of PVS1 (very strong) and PM2 (supporting) for pathogenicity against BP4 (supporting) for benignity leaves conflicting evidence under the generic ACMG/AMP 2015 rules.

Final determination: Conflicting pathogenic (PVS1+PM2) and benign (BP4) evidence defaults to VUS under generic ACMG/AMP 2015 rules.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met (Very Strong): the nonsense variant p.(Glu260Ter) is predicted to trigger nonsense-mediated decay, consistent with a null NF2 allele.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not applicable: as a nonsense variant, no altered amino acid exists at this position to compare against previously established pathogenic variants.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no confirmed de novo occurrence is documented; parental testing and phenotype information were not available.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no validated functional assay specific to this variant was available.
PS4	Not assessed	Not assessed: no affected-case counts, controls, or variant-specific case series were available.
PM1	N/A	Not applicable: as a nonsense variant, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: NF2-related schwannomatosis is autosomal dominant, so the recessive trans-phase criterion does not apply.	PMID:19545378
PM4	N/A	Not applicable: as a nonsense variant, no protein length change occurs, leaving nothing for this length-change criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a different pathogenic missense change.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no parental testing or case-level information supporting a de novo occurrence was available.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family segregation data or informative meioses were available.	generic_acmg_combination_rules
PP2	N/A	Not applicable: the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.149 is below the ~0.2 cutoff for a likely splice-altering effect.	spliceai
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnostic criteria were available to evaluate phenotype specificity.
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic classification is documented for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency reaches the standalone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population datasets, so no allele frequency exceeds the expected rate for NF2-related disease.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy-adult cohort or unaffected-control observation of this variant was available.
BS3	Not assessed	Not assessed: no functional assay evidence of a benign effect for this specific variant was available.
BS4	Not assessed	Not assessed: no unaffected relatives with reliable genotypes were available to demonstrate lack of segregation.	generic_acmg_combination_rules
BP1	N/A	Not applicable: the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or phase information was available to evaluate trans configuration.
BP3	N/A	Not applicable: as a nonsense variant, no in-frame length change occurs within a repetitive region to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.149 is below the ~0.2 cutoff, predicting no significant splice disruption.	spliceai
BP5	Not assessed	Not assessed: no evidence that the phenotype is explained by an alternative molecular cause was available.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign classification is documented for this exact variant.	clinvar
BP7	N/A	Not applicable: the variant is not synonymous, so the silent-variant premise of this criterion does not hold.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.