Variant classification summary

NM_000268.3:c.958C>T

NF2 · NP_000259.1:p.(Gln320Ter) · NM_000268.3

GRCh37: chr22:30064394 C>T · GRCh38: chr22:29668405 C>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.(Gln320Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): the p.Gln320Ter premature stop codon lies ~780 nucleotides upstream of the final exon-exon junction, predicting nonsense-mediated decay.

2

PM2 (Supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

3

BP4 (Supporting): SpliceAI max delta 0.003 predicts no splice disruption.

4

Overall: VUS - PVS1 (very strong) and PM2 (supporting) would reach likely pathogenic, but conflicting BP4 (supporting) holds the result at VUS.

Final determination:

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: 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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	N/A	Not applicable: the variant is a stop-gain, so no altered amino acid exists to compare against a previously established pathogenic missense.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental testing results or documented de novo observation were available.
PS3	Not assessed	Not assessed: no functional assay data for this variant were available.
PS4	Not assessed	Not assessed: no case series or case-control comparison demonstrating increased prevalence in affected individuals was available.	clinvar PMID:7913580
PM1	N/A	Not applicable: PM1 requires a missense variant, and this stop-gain produces no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada PMID:19545378
PM3	N/A	Not applicable: NF2-related disease is autosomal dominant, so the recessive in-trans requirement does not apply.
PM4	N/A	Not applicable: this stop-gain does not change protein length, so PM4 has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at codon 320 to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no unconfirmed de novo observation was documented.
PP1	Not assessed	Not assessed: no affected relatives, segregation data, or informative meioses were provided.
PP2	N/A	Not applicable: PP2 concerns missense variants, and this stop-gain has no missense change to evaluate.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.003 predicts no splice disruption, and no other computational evidence supports a damaging effect.	spliceai
PP4	Not assessed	Not assessed: no patient-specific phenotype data were available to confirm a highly specific NF2 presentation.
PP5	Not met	Not met: no expert-panel ClinVar submission exists for this variant, and laboratory or OMIM classifications cannot trigger PP5.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, far below any stand-alone benign frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from population databases, below the disease-specific maximum credible allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no evidence of occurrence in healthy adults or homozygous individuals was provided.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence of normal activity was available.
BS4	Not assessed	Not assessed: no unaffected relatives or non-segregation analysis was reported.
BP1	N/A	Not applicable: BP1 concerns missense variants, and this stop-gain has no missense change to evaluate.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or phase determination was available to assess allelic arrangement.
BP3	N/A	Not applicable: this stop-gain does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met: SpliceAI max delta 0.003 is far below the ~0.2 splice-altering threshold, predicting no splice impact.	spliceai
BP5	Not assessed	Not assessed: insufficient evidence linked this variant to an alternate phenotype or disease mechanism.
BP6	Not met	Not met: no expert-panel ClinVar classification of Benign or Likely benign exists for this variant.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this stop-gain changes the encoded protein.	generic_acmg_combination_rules

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