Classification rationale

PM2 BP4 VUS

NF1 c.2190C>G missense · exon 18

PM2 (Supporting): the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BP4 (Supporting): SpliceAI max delta 0.002 and REVEL 0.06 both predict a benign effect. Classification: VUS - PM2 and BP4 at supporting strength are insufficient to reach the pathogenic or benign thresholds under the generic ACMG/AMP 2015 combination rules.

PM2 + BP4 → VUS

Gene diagram · NM_001042492.2 · variants mapped to exon structure

NF1 NM_001042492.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

The exact variant NM_001042492.2:c.2190C>G / NP_001035957.1:p.(Asn730Lys) is reported as absent from gnomAD v2.1.The exact variant is reported as absent from gnomAD v4.1.The exact variant is reported as absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.002 and REVEL 0.06 both predict a benign effect.

CSpec NF1 VCEP framework (doc 1553923915) has no gene-specific PP3/BP4 lookup table or rule_payload (framework_complete false), so generic ACMG BP4 logic applies.SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00)'; individual deltas DS_AG=0.0, DS_AL=0.002, DS_DG=0.001, DS_DL=0.001 are all far below any splice-disruption threshold, supporting BP4 via the splice-impact path.REVEL score 0.06 (source_registry 'revel') is low and, per the published ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID 36413997), falls in the benign-supporting range for the missense in-silico path.

cspec ↗spliceai ↗

Assessed · not applied · 8 not met · 14 not assessed

Pathogenic

PS1 Not met: no ClinVar record exists for this variant or any alternate codon producing p.Asn730Lys.

PS2 Not assessed: no proband de novo observation or parental genotype data was available.

PS3 Not assessed: no functional assay data (e.g., Ras-GAP activity) for this variant was available.

PS4 Not assessed: no affected-case series or case-control enrichment data was available.

PM1 Not met: residue N730 lies in the N-HEAT scaffolding domain, not the GRD/RasGAP region containing the catalytic hotspot.

PM3 Not assessed: no second pathogenic allele, phase information, or segregation data was available.

PM5 Not assessed: no different missense change at Asn730 previously established as pathogenic was available.

PM6 Not assessed: no case report documenting the variant as presumed de novo was available.

PP1 Not assessed: no affected relatives or cosegregation observations were documented.

PP2 Not met: NF1 is predominantly truncating (48% nonsense vs 13% missense in one cohort), so missense is not a common disease mechanism.

PP3 Not met: SpliceAI max delta 0.002 and REVEL 0.06 both predict no damaging effect.

PP4 Not assessed: no patient phenotype or clinical features for this variant were available.

PP5 Not met: the variant is absent from ClinVar with no expert-panel classification.

Benign

BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, so no allele frequency exceeds the stand-alone benign threshold.

BS1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, so no allele frequency exceeds a disease-specific benign threshold.

BS2 Not assessed: no observations of unaffected homozygous adults for this variant were available.

BS3 Not assessed: no functional assay data demonstrating normal neurofibromin function was available.

BS4 Not assessed: no unaffected relatives tested for the variant were documented.

BP1 Not assessed: NF1 is predominantly truncating, but recurrent pathogenic missense in the GRD region prevents a reliable determination.

BP2 Not assessed: no observation of the variant in cis with a pathogenic variant or phase data was available.

BP5 Not assessed: no data establishing an alternative molecular cause was available.

BP6 Not met: the variant is absent from ClinVar with no expert-panel classification.

N/A · 4 PVS1 · PM4 · BP3 · 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 = 0.06. BayesDel score = -0.61216.

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. NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.

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

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots