Variant classification summary

NM_000268.3:c.863C>G

NF2 · NP_000259.1:p.(Ser288Ter) · NM_000268.3

GRCh37: chr22:30061031 C>G · GRCh38: chr22:29665042 C>G

Gene: NF2 Transcript: NM_000268.3

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Ser288Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): Nonsense p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay.

2

PM2 (Supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, three large population cohorts.

3

Together, PVS1 (very strong) plus PM2 (supporting) yields Likely Pathogenic under the ClinGen SVI 2020 combination rule (posterior probability 0.988).

Final determination: Generic ACMG/AMP 2015 fallback: PVS1 (very strong) + PM2 (supporting) = 1 very strong + 1 supporting, which is Likely Pathogenic under the ClinGen SVI 2020 PM2-downgrade addendum (PVS1 + 1 supporting criterion -> Likely Pathogenic, Post_P 0.988); the combination does not satisfy any Pathogenic rule (no 1 strong, no 2 moderate, and no 1 moderate + 1 supporting or 2 supporting alongside PVS1).

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): Nonsense change p.Ser288Ter truncates merlin at 288 of 595 amino acids and is predicted to trigger nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:25741868 PMID:9643284 PMID:19545378 gnomad_v2 gnomad_v4 gnomad_canada spliceai
PS1	N/A	Not applicable: as a nonsense change producing a stop codon, no altered amino acid exists to compare against a known pathogenic missense at this position.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence report or parental genotype data were available for this variant.	generic_acmg_combination_rules clinvar
PS3	Not assessed	Not assessed: no validated functional assay specific to this variant was available to demonstrate a damaging effect.	PMID:25741868 oncokb PMID:9643284 PMID:19545378 PMID:22825583 PMID:8755919 generic_acmg_combination_rules
PS4	Not met	Not met: no case-control or cohort prevalence study exists; the only observation is a single laboratory submission, short of the multiple-unrelated-patients requirement.	clinvar PMID:25741868
PM1	N/A	Not applicable: no altered residue exists to evaluate, as this is a nonsense change rather than a missense variant.	generic_acmg_combination_rules
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, three large population cohorts, in a gene with an established loss-of-function disease mechanism.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: this criterion applies only to recessive disorders, and NF2-related schwannomatosis is autosomal dominant.	PMID:25741868 PMID:19545378
PM4	N/A	Not applicable: no protein length change occurs, so this criterion for in-frame insertions/deletions or stop-loss variants does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare against a previously pathogenic missense at the same position.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no unconfirmed de novo report or parental testing data were available for this variant.	generic_acmg_combination_rules clinvar
PP1	Not assessed	Not assessed: no co-segregation data in affected family members were available for this variant.	generic_acmg_combination_rules clinvar
PP2	N/A	Not applicable: no missense change is present, so the gene's missense-constraint properties are not relevant to this variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: as a nonsense change, the truncating effect is established directly from the sequence; SpliceAI max delta 0.00 shows no competing splice effect.	spliceai bayesdel generic_acmg_combination_rules
PP4	Not met	Not met: no proband phenotype or family-history documentation was available to establish a highly specific phenotype.	clinvar PMID:25741868
PP5	Not met	Not met: the only ClinVar submission is a single 1-star laboratory classification, not an expert-panel classification as this criterion requires.	clinvar PMID:25741868
BA1	Not met	Not met: allele frequency is zero (absent from gnomAD v2.1, v4.1, and gnomAD-Canada), far below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: allele frequency zero (absent from all three gnomAD cohorts) is far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada PMID:19545378
BS2	Not met	Not met: no heterozygous or homozygous observations exist in population cohorts, so no healthy-adult carrier evidence is available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional study demonstrating preserved protein function or splicing was available for this variant.	PMID:25741868 spliceai oncokb PMID:9643284 generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family genotype data were available to evaluate whether segregation is contradicted in affected relatives.	generic_acmg_combination_rules clinvar
BP1	N/A	Not applicable: no missense change is present, so this criterion for missense variants in genes with primarily truncating disease mechanisms does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no parental or family data were available to determine whether the variant lies in cis or trans with a pathogenic variant.	clinvar PMID:25741868
BP3	N/A	Not applicable: no in-frame insertion or deletion in a repetitive region is present to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the nonsense change definitively impacts the gene product, and SpliceAI's no-splice-impact prediction (0.00) does not show overall benignity.	spliceai generic_acmg_combination_rules
BP5	Not met	Not met: no alternate genetic cause of disease was documented for this variant.	PMID:25741868
BP6	Not met	Not met: no benign or likely-benign ClinVar assertion exists for this variant, and only expert-panel classifications qualify for this criterion.	clinvar PMID:25741868
BP7	N/A	Not applicable: this criterion applies only to synonymous variants, and this is a nonsense change.	generic_acmg_combination_rules

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