NM_000268.3:c.1408C>G

NF2 · NP_000259.1:p.(Gln470Glu) · NM_000268.3

GRCh37: chr22:30070892 C>G · GRCh38: chr22:29674903 C>G

Gene: NF2 Transcript: NM_000268.3

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

NF2

Transcript

NM_000268.3

Protein

NP_000259.1:p.(Gln470Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

Variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at moderate strength.

REVEL (0.314), BayesDel (-0.283), and SpliceAI (max delta 0.00) each predict a neutral effect, satisfying BP4 at supporting strength.

Overall classification: one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) results in a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	Missense substitution (c.1408C>G, p.Gln470Glu) is not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 decision framework (PMC6185798) does not apply to this variant class.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No pathogenic variant with the identical amino acid change (p.Gln470Glu) has been established in ClinVar or the available literature.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity status has been identified for this variant.
PS3	Not met	No functional studies have directly tested NM_000268.3:c.1408C>G (p.Gln470Glu) or systematically characterized the residue range encompassing position 470. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence.	oncokb
PS4	Not met	No case-control or prevalence data are available to demonstrate enrichment of this variant in affected individuals versus controls.	clinvar
PS5	Not met	Variant has not been reported in multiple unrelated patients with the same phenotype and absent from ClinVar.	clinvar
PM1	Not met	cancerhotspots.org does not identify a statistically significant mutation hotspot at residue 470. While position 470 lies within the coiled-coil domain of merlin (aa 303-478), no domain-level functional data or missense constraint evidence specific to this domain was retrieved in the case materials to support PM1.
PM2	Met	Absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the allele frequency threshold of <0.1% for PM2 under generic ACMG/AMP criteria.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator missense variant with established pathogenicity was identified. PM5 candidate search returned zero candidates at codon 470.	pm5_candidates
PM6	Not met	No de novo observation (assumed or confirmed) has been reported for this variant.
PP1	Not met	No cosegregation data with disease phenotype in multiple affected family members is available for this variant.
PP2	Not met	HCI prior score is not available for NF2 (gene not supported). Without gene-specific missense constraint metrics (e.g., missense Z-score), the low rate of benign missense variation required for PP2 cannot be established.
PP3	Not met	REVEL score 0.314 is below the pathogenic threshold (>0.5), BayesDel score -0.282509 is in the benign range, and SpliceAI max delta score is 0.00 (no predicted splice impact). Multiple lines of computational evidence do not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data has been provided for this variant. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and the literature.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% population allele frequency threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from all population databases. Does not meet the >0.3% allele frequency threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adults.
BS3	Not met	No well-established functional studies demonstrating a neutral or benign effect have been performed on this variant.
BS4	Not met	No segregation data are available to assess lack of cosegregation with disease in affected families.
BP1	Not met	Although NF2-related schwannomatosis is driven by loss-of-function, missense pathogenic variants are also an established disease mechanism in NF2. BP1 applies only when a gene's disease is caused primarily by truncating variants and missense variants are unlikely to be pathogenic.	pvs1_gene_context
BP2	Not met	No data are available on observation of this variant in trans with a known pathogenic variant for NF2-related schwannomatosis.
BP4	Met	REVEL score 0.314 is below the pathogenic threshold (>0.5), BayesDel score -0.282509 is in the benign range (negative), and SpliceAI predicts no splice impact (max delta score 0.00). Multiple lines of computational evidence suggest no deleterious effect on the gene product.	revel bayesdel spliceai
BP5	Not met	No case has been reported where this variant is found alongside an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (c.1408C>G, p.Gln470Glu); BP7 applies only to synonymous (silent) variants with no predicted splice impact.

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.