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NM_000268.3:c.363+1G>C
p.? · NF2
ACMG/AMP
0%
complete
Final classification
VUS
PM2
NF2
c.363+1G>C
p.?
canonical splice
Gene context NCBI Gene ↗ OncoKB ↗

NF2 encodes Merlin, a scaffolding protein that links the cell's internal skeleton to the cell membrane and helps regulate cell growth, adhesion, and signaling. Loss of its function promotes tumor formation and spread. Germline mutations in this gene cause neurofibromatosis type 2, an inherited condition marked by tumors of the nervous system and skin, along with eye abnormalities. It acts as a tumor suppressor, and the gene is also found mutated in other types of cancer.

This variant

NF2 is a tumor suppressor whose loss promotes tumor formation and causes neurofibromatosis type 2, so a splice-disrupting change in this gene would be expected to be pathogenic. This canonical splice-donor variant is classified as a VUS: SpliceAI predicts near-certain donor loss (delta 0.99), but loss-of-function is not yet formally confirmed and only its absence from gnomAD currently supports the call.

Transcript
NM_000268.3
HGVS · transcript:coding
NM_000268.3:c.363+1G>C
GRCh38
chr22:29639213 G>C
GRCh37
chr22:30035202 G>C
Variant of Uncertain Significance: only PM2 (Supporting) is met, and a single supporting criterion satisfies no pathogenic or benign combination under generic ACMG/AMP 2015.
Classification rationale
PM2 VUS
NF2 c.363+1G>C canonical splice

PM2 (Supporting): absent (AF=0) from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes. Overall: Variant of Uncertain Significance - one supporting criterion (PM2) satisfies no combination under generic ACMG/AMP 2015.

PM2 → VUS
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.
Gene diagram · NM_000268.3 · variants mapped to exon structure
NF2 NM_000268.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 18 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 · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met (Supporting): absent (AF=0) from gnomAD v2.1/v4.1 exomes and gnomAD-Canada genomes.
gnomAD v2.1 exome: absent (AF=0)gnomAD v4.1 exome: absent (AF=0)gnomAD-Canada v1.0 genome: absent (AF=0)
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
Assessed · not applied · 8 not met · 10 not assessed
Pathogenic
PVS1 Not assessed: insufficient evidence was available to confirm loss-of-function for this canonical splice-donor variant.
PS2 Not assessed: no proband or parental genotype data was available to test for a de novo occurrence.
PS3 Not assessed: no functional (RNA or protein) studies of this variant were available.
PS4 Not met: no germline case-control or case-series enrichment data exists for this variant.
PM6 Not assessed: no de novo occurrence of this variant is reported in any source.
PP1 Not assessed: no segregation data in affected family members is available for this variant.
PP3 Not met: SpliceAI predicts near-certain splice disruption (delta 0.99), but the same splice-effect prediction is already captured under PVS1, so PP3 is not awarded.
PP4 Not assessed: no proband phenotype or family-history data was available to evaluate a gene-specific presentation.
PP5 Not met: ClinVar has no record for this variant, so no expert-panel pathogenic classification exists.
Benign
BA1 Not met: allele frequency is 0 across gnomAD v2.1/v4.1 exomes and gnomAD-Canada, far below the >1% threshold.
BS1 Not met: absent from gnomAD (AF=0), below the >0.3% threshold expected for this disorder.
BS2 Not met: no healthy adult carriers or homozygotes were observed in population cohorts (AF=0).
BS3 Not assessed: no functional studies showing absence of a damaging effect were available.
BS4 Not assessed: no segregation or non-segregation observations were available.
BP2 Not assessed: no cis/trans phase observations were available.
BP4 Not met: no computational line supports no impact; SpliceAI predicts near-certain splice disruption (delta 0.99).
BP5 Not assessed: no proband-level data was available to determine whether an alternate molecular basis explained the phenotype.
BP6 Not met: ClinVar has no record for this variant, so no expert-panel benign classification exists.
N/A · 9 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.66.
SpliceAI ↗
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV58527414, n = 2 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
7Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC