NM_000268.3:c.1249A>T

NF2 · NP_000259.1:p.(Ile417Phe) · NM_000268.3

GRCh37: chr22:30069384 A>T · GRCh38: chr22:29673395 A>T

Gene: NF2 Transcript: NM_000268.3

Final call

VUS

PM2 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Ile417Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): variant absent (AF = 0) from gnomAD v2.1, v4.1, and gnomAD-Canada.

With PM2 as the only criterion met, no ACMG/AMP 2015 pathogenic, likely pathogenic, benign, or likely benign combination threshold is reached; classification is Variant of Uncertain Significance.

Final determination: Under generic ACMG/AMP 2015 fallback rules (no NF2 VCEP/CSPEC exists), a single supporting criterion (PM2 supporting) satisfies no benign (BA1 alone or 2 BS), likely benign (1 BS+1 BP or 2 BP), likely pathogenic (e.g., 3 PM, 2 PM+2 PP, 1 PM+4 PP, 1 PS+1 PM, PVS1+1 PM), or pathogenic (e.g., 2 PS, 1 PS+3 PM, PVS1+1 PS) combination, so 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	N/A	Not applicable: PVS1 applies only to null variants — nonsense, frameshift, or splice-site — and this is a missense change.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no established pathogenic variant producing the same amino acid change (p.Ile417Phe) exists in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband, parental, or family genotype data were available, so a de novo occurrence could not be evaluated.	generic_acmg_combination_rules clinvar
PS3	Not assessed	Not assessed: no variant-specific functional assay data (e.g., merlin localization or growth-suppression assays) were available.	oncokb clinvar
PS4	Not assessed	Not assessed: no affected cases or case-control cohort data exist for this variant, so prevalence-based enrichment cannot be evaluated.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM1	Not met	Not met: residue Ile417 shows no evidence of lying in a mutational hotspot or critical functional domain.	oncokb
PM2	Met	Met (Supporting): allele frequency is 0 — the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the <0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: PM3 applies only to recessive disorders, and NF2-related schwannomatosis is autosomal dominant.	pvs1_gene_context
PM4	N/A	Not applicable: PM4 applies to in-frame indels or stop-loss protein-length changes, and this missense does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not met	Not met: no different missense at codon 417 is established as pathogenic, and no same-residue candidates were found.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no observation of the variant arising de novo was available in any evidence source.	generic_acmg_combination_rules clinvar
PP1	Not assessed	Not assessed: no family or pedigree data were available, so co-segregation could not be evaluated.	generic_acmg_combination_rules
PP2	Not met	Not met: loss-of-function, not missense, is the established NF2 disease mechanism, and no missense constraint metric was collected.	pvs1_gene_context oncokb
PP3	Not met	Not met: REVEL 0.436 is below the 0.644 PP3 threshold, and SpliceAI max delta 0.02 predicts no splice impact.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no proband phenotype or family history was available, so phenotype specificity could not be evaluated.	clinvar
PP5	Not met	Not met: ClinVar has no record of this variant, so no expert-panel pathogenic classification exists to support PP5.	clinvar
BA1	Not met	Not met: allele frequency is 0, far below the >5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: allele frequency is 0, below the >0.3% BS1 threshold and any frequency expected for this rare disorder.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy-adult carriers were observed (AF 0), and the disorder's adult onset means early full penetrance does not apply.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional assay evidence demonstrating an absence of damaging effect was available.	oncokb spliceai clinvar
BS4	Not assessed	Not assessed: no family genotype data were available, so lack of segregation in affected relatives could not be evaluated.	generic_acmg_combination_rules
BP1	Not met	Not met: NF2-related schwannomatosis is caused by diverse alterations including non-truncating variants, not truncating changes only.	pvs1_gene_context oncokb
BP2	Not met	Not met: no documented cis or trans observation of this variant with a pathogenic variant exists.	clinvar
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, and this is a missense change.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only one no-impact line (SpliceAI max delta 0.02) is available, while BP4 requires multiple; REVEL 0.436 is indeterminate.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: the variant has never been reported in a case, so an alternate molecular basis could not be evaluated.	clinvar
BP6	Not met	Not met: ClinVar has no record of this variant, so no expert-panel benign classification exists to support BP6.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants with no predicted splice impact, and this is a missense change.	generic_acmg_combination_rules

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