Classification rationale

PM2 BP4 VUS

NF2 c.1408C>G

Variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying PM2 at moderate strength.¹ REVEL (0.314), BayesDel (-0.283), and SpliceAI (max delta 0.00) each predict a neutral effect, satisfying BP4 at supporting strength.² 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.³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_000268.3 · variants mapped to exon structure

NF2 NM_000268.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate review Pathogenic

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.

Absent from gnomAD v2.1 (AF: null/absent)gnomAD v4.1 (AF: null/absent)gnomAD-Canada v1.0 (AC=0).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

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 0.314 (not deleterious)BayesDel -0.282509 (benign)SpliceAI max delta 0.00 (no splice impact).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic variant with the identical amino acid change (p.Gln470Glu) has been established in ClinVar or the available literature.

PS2 No de novo observation with confirmed paternity and maternity status has been identified for this variant.

PS3 No functional studies have directly tested NM_000268.3:c.1408C>G (p.Gln470Glu) or systematically characterized the residue range encompassing position 470.

PS4 No case-control or prevalence data are available to demonstrate enrichment of this variant in affected individuals versus controls.

PM1 cancerhotspots.org does not identify a statistically significant mutation hotspot at residue 470.

PM5 No same-residue comparator missense variant with established pathogenicity was identified.

PM6 No de novo observation (assumed or confirmed) has been reported for this variant.

PP1 No cosegregation data with disease phenotype in multiple affected family members is available for this variant.

PP2 HCI prior score is not available for NF2 (gene not supported).

PP3 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).

PP4 No patient phenotype or family history data has been provided for this variant.

PP5 No reputable source has recently reported this variant as pathogenic.

Benign

BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 Variant is absent from all population databases.

BS2 No data are available regarding observation of this variant in healthy adults.

BS3 No well-established functional studies demonstrating a neutral or benign effect have been performed on this variant.

BS4 No segregation data are available to assess lack of cosegregation with disease in affected families.

BP1 Although NF2-related schwannomatosis is driven by loss-of-function, missense pathogenic variants are also an established disease mechanism in NF2.

BP2 No data are available on observation of this variant in trans with a known pathogenic variant for NF2-related schwannomatosis.

BP5 No case has been reported where this variant is found alongside an alternate molecular basis for disease.

BP6 No reputable source has reported this variant as benign.

N/A · 2 PVS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.314. BayesDel score = -0.282509.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF2, a scaffolding protein, is frequently altered in mesothelioma, meningioma and nerve sheath tumors.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots