NM_000268.3:c.363+1G>C

NF2 · NP_000259.1:p.? · NM_000268.3

GRCh37: chr22:30035202 G>C · GRCh38: chr22:29639213 G>C

Gene: NF2 Transcript: NM_000268.3

Final call

VUS

PM2 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent (AF=0) from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes.

Overall: Variant of Uncertain Significance - one supporting criterion (PM2) satisfies no combination under generic ACMG/AMP 2015.

Final determination: Generic ACMG/AMP 2015 combination rule: no Pathogenic (PVS1+PS/PM/PP, 2 PS, or PS+3PM/2PM+2PP/1PM+4PP), Likely Pathogenic (PVS1+PM, PVS1+PP, PS+PM, PS+2PP, 3 PM, 2PM+2PP, 1PM+4PP), Benign (BA1 or 2 BS), or Likely Benign (1 BS+1 BP or 2 BP) combination is satisfied with only PM2 supporting; therefore the variant is classified as Variant of Uncertain Significance.

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	Not assessed	Not assessed: insufficient evidence was available to confirm loss-of-function for this canonical splice-donor variant. Flagged for human review: SpliceAI predicts near-certain donor loss (delta 0.99).
PS1	N/A	Not applicable: as a splice-site variant producing no altered amino acid, no residue exists to compare with established pathogenic missense changes.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental genotype data was available to test for a de novo occurrence.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional (RNA or protein) studies of this variant were available.	generic_acmg_combination_rules spliceai clinvar
PS4	Not met	Not met: no germline case-control or case-series enrichment data exists for this variant.	clinvar generic_acmg_combination_rules
PM1	N/A	Not applicable: as a splice-site variant, no altered residue exists to evaluate for hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Supporting): absent (AF=0) from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes.	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
PM3	N/A	Not applicable: NF2-related schwannomatosis is autosomal dominant, so the recessive in-trans requirement does not apply.	generic_acmg_combination_rules pvs1_gene_context
PM4	N/A	Not applicable: this splice-site variant produces no in-frame or stop-loss protein length change.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this position to compare with a different pathogenic missense change.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence of this variant is reported in any source.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no segregation data in affected family members is available for this variant.	clinvar generic_acmg_combination_rules
PP2	N/A	Not applicable: applies only to missense variants; this is a splice-consensus variant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI predicts near-certain splice disruption (delta 0.99), but the same splice-effect prediction is already captured under PVS1, so PP3 is not awarded.	spliceai bayesdel pvs1_variant_assessment pvs1_generic_framework generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history data was available to evaluate a gene-specific presentation.	generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar has no record for this variant, so no expert-panel pathogenic classification exists.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: allele frequency is 0 across gnomAD v2.1/v4.1 exomes and gnomAD-Canada, far below the >1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: absent from gnomAD (AF=0), below the >0.3% threshold expected for this disorder.	gnomad_v2 gnomad_v4 gnomad_canada pvs1_gene_context generic_acmg_combination_rules
BS2	Not met	Not met: no healthy adult carriers or homozygotes were observed in population cohorts (AF=0).	gnomad_v2 gnomad_v4 gnomad_canada clinvar
BS3	Not assessed	Not assessed: no functional studies showing absence of a damaging effect were available.	generic_acmg_combination_rules spliceai clinvar
BS4	Not assessed	Not assessed: no segregation or non-segregation observations were available.	clinvar generic_acmg_combination_rules
BP1	N/A	Not applicable: applies only to missense variants; this is a canonical splice-donor variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase observations were available.	generic_acmg_combination_rules clinvar
BP3	N/A	Not applicable: the variant does not alter protein length in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: no computational line supports no impact; SpliceAI predicts near-certain splice disruption (delta 0.99).	spliceai bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data was available to determine whether an alternate molecular basis explained the phenotype.	generic_acmg_combination_rules
BP6	Not met	Not met: ClinVar has no record for this variant, so no expert-panel benign classification exists.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: defined for synonymous variants; this variant alters the encoded protein sequence.	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.