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NF2c.1408C>GUncertain significance
Print report
Variant interpretation report

NF2 c.1408C>G, p.(Gln470Glu)

NM_000268.3:c.1408C>G NP_000259.1:p.(Gln470Glu) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About NF2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 ModerateAbsent 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF: null/absent)
  • gnomAD v4.1 (AF: null/absent)
  • gnomAD-Canada v1.0 (AC=0).
Still missing
  • gnomAD v2.1 and v4.1 allele number (AN) values are null in evidence_brief
  • confirm the variant position is adequately covered in these population databases to ensure absence is meaningful rather than a coverage gap.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.314 (not deleterious)
  • BayesDel -0.282509 (benign)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No pathogenic variant with the identical amino acid change (p.Gln470Glu) has been established in ClinVar or the available literature. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no same-amino-acid comparator with established pathogenicity identified.
Still missing
  • No literature reports of p.Gln470Glu as a pathogenic variant.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity status has been identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports found in ClinVar
  • literature_pass
  • or PVS1 gene-context literature.
Still missing
  • No parental testing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional data
  • not in COSMIC
  • cancerhotspots.org reports no significant hotspot at this residue.
Still missing
  • No experimental functional characterization of p.Gln470Glu or the encompassing domain available.
Sources
oncokb ↗
PS4 No case-control or prevalence data are available to demonstrate enrichment of this variant in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no affected-vs-control comparison data in evidence packet.
Still missing
  • No case-control studies or prevalence data for this variant.
Sources
clinvar ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue_significant=false
  • exact_variant_listed=no. Coiled-coil domain location noted but no domain-specific constraint evidence in the case materials.
Still missing
  • Domain-level functional criticality of the coiled-coil region for NF2 pathogenesis has not been assessed with curated evidence.
PM5 No same-residue comparator missense variant with established pathogenicity was identified. PM5 candidate search returned zero candidates at codon 470. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 total candidates
  • 0 same-residue candidates
  • 0 expert panel P/LP candidates.
Still missing
  • No ClinVar entries for any missense variant at codon 470.
Sources
pm5_candidates
PM6 No de novo observation (assumed or confirmed) has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar or the literature packet.
Still missing
  • No parental testing or de novo reports available.
PP1 No cosegregation data with disease phenotype in multiple affected family members is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family studies or cosegregation data in the case materials.
Still missing
  • No pedigree or family-based genetic data available.
PP2 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. Details ▾Hide ▴
Evidence considered
  • HCI prior: not found (gene_not_supported). No alternative missense constraint metrics in the case materials.
Still missing
  • Missense constraint data (Z-score
  • observed/expected ratio) for NF2 not retrieved
  • PP2 application requires evidence that NF2 has a low rate of benign missense variation.
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). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.314 (below pathogenic threshold)
  • BayesDel -0.282509 (benign range)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No patient-specific phenotype data in case materials.
Still missing
  • Patient phenotype and clinical history not available.
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and the literature. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no published reports of pathogenicity.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% population allele frequency threshold for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
  • allele frequency is effectively 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from all population databases. Does not meet the >0.3% allele frequency threshold for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
  • allele frequency is effectively 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available regarding observation of this variant in healthy adults. Details ▾Hide ▴
Evidence considered
  • No healthy control data in case materials.
Still missing
  • No observation data in healthy adult controls.
BS3 No well-established functional studies demonstrating a neutral or benign effect have been performed on this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available for this variant. OncoKB reports Unknown Oncogenic Effect with no functional annotation.
Still missing
  • No benign functional evidence available.
BS4 No segregation data are available to assess lack of cosegregation with disease in affected families. Details ▾Hide ▴
Evidence considered
  • No family studies in the case materials.
Still missing
  • No pedigree or segregation analysis available.
BP1 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. Details ▾Hide ▴
Evidence considered
  • NF2 LoF mechanism confirmed in germline disease
  • however
  • missense variants are a well-documented pathogenic mechanism in NF2-related schwannomatosis
  • precluding BP1 application.
Sources
pvs1_gene_context
BP2 No data are available on observation of this variant in trans with a known pathogenic variant for NF2-related schwannomatosis. Details ▾Hide ▴
Evidence considered
  • No allele-phase data in the case materials.
Still missing
  • No trans-phase data with pathogenic variants.
BP5 No case has been reported where this variant is found alongside an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No data on alternate molecular diagnoses in carriers of this variant.
Still missing
  • No alternate molecular basis data available.
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classifications from any submitter.
Sources
clinvar ↗
PS5 Variant has not been reported in multiple unrelated patients with the same phenotype and absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • No ClinVar submissions
  • no credible reports of this variant in affected individuals.
Still missing
  • No patient observations reported.
Sources
clinvar ↗
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense 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. Details ▾Hide ▴
Evidence considered
  • Variant class: missense
  • variant_bucket='other'
  • apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
BP7 N/AThis is a missense variant (c.1408C>G, p.Gln470Glu); BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.

Identifiers

Gene
NF2
Transcript
NM_000268.3
Coding (HGVS c.)
NM_000268.3:c.1408C>G
Protein (HGVS p.)
NP_000259.1:p.(Gln470Glu)
GRCh38
chr22:29674903 C>G
GRCh37
chr22:30070892 C>G

Gene diagram

Every interpreted variant in NF2, mapped onto the exon structure of NM_000268.3. Select a row to find it on the plot.

NF2NM_000268.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -419 bp
0.000
SpliceAI acceptor gainat -59 bp
0.000
SpliceAI donor lossat +165 bp
0.000
SpliceAI donor gainat -327 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.314
BayesDel
-0.283

How the predictions were used

BP4 SupportingREVEL 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.314 (not deleterious)
  • BayesDel -0.282509 (benign)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
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). Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.314 (below pathogenic threshold)
  • BayesDel -0.282509 (benign range)
  • SpliceAI max delta 0.00 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.1408C>G, p.Gln470Glu); BP7 applies only to synonymous (silent) variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not synonymous.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from 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.

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.