NM_024408.3:c.3570G>C (p.Glu1190Asp) in NOTCH2 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a rare variant interpretation.1 Multiple in silico predictors suggest no significant impact: BayesDel predicts a benign score (-0.045) and SpliceAI indicates no splicing impact (max delta 0.07).2 The variant is a novel missense change at a residue not in a known functional domain or mutational hotspot. No functional studies, segregation data, or de novo reports are available.3 Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting pathogenic) and BP4 (supporting benign) are both met. The single supporting pathogenic and single supporting benign criterion do not reach the threshold for Likely Pathogenic or Likely Benign.4 This variant is classified as a Variant of Uncertain Significance (VUS).5
NOTCH2
Final classification
VUS
PM2BP4
NOTCH2
c.3570G>C
p.Glu1190Asp
This variant
NM_024408.3:c.3570G>C (p.Glu1190Asp) in NOTCH2 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a rare variant interpretation.
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 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
NOTCH2 c.3570G>C
PM2 + BP4
→
VUS
Gene diagram
· NM_024408.3 · variants mapped to exon structure
NOTCH2
NM_024408.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 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
NM_024408.3:c.3570G>C is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from population databases meets PM2 at supporting strength.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes + genomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
BP4
supporting
review
Benign
Multiple lines of computational evidence suggest no impact on gene product: BayesDel score -0.045 is below 0 (predicted benign) and SpliceAI max delta score 0.07 indicates no splicing impact. REVEL score 0.567 is marginally above 0.5, but the overall in silico consensus favors a benign interpretation (2 of 3 tools predict benign/no impact).
BayesDel: -0.045 (predicted benign).SpliceAI max delta: 0.07 (no splicing impact).REVEL: 0.567 (borderline
Assessed · not applied
· 21 not met · 0 not assessed
Pathogenic
PVS1
NM_024408.3:c.3570G>C is a missense variant (p.Glu1190Asp) and does not fall into any ClinGen SVI PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus).
PS1
No previously established pathogenic variant at residue 1190 with the same amino acid change (p.Glu1190Asp) was identified.
PS2
No de novo observation with confirmed paternity and maternity is available for this variant.
PS3
No well-established in vitro or in vivo functional studies were identified for this variant.
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals is available.
PM1
Residue 1190 does not fall within a statistically significant mutational hotspot (CancerHotspots negative).
PM6
No de novo observation (without confirmation of paternity and maternity) is available for this variant.
PP1
No cosegregation data in affected families is available for this variant.
PP2
NOTCH2 missense constraint data are not available (HCI prior not found).
PP3
In silico predictions are discordant.
PP4
No patient phenotype or family history data are available; the variant was assessed as a standalone laboratory finding.
PP5
No reputable source has reported this variant as pathogenic; it is absent from ClinVar.
Benign
BA1
NM_024408.3:c.3570G>C is absent from all population databases.
BS1
The variant is absent from all population databases.
BS2
No homozygous or hemizygous observations in healthy adults, and no trans observation with a known pathogenic variant, are available.
BS3
No well-established functional studies showing no damaging effect are available for this variant.
BS4
No segregation data showing lack of cosegregation with disease is available.
BP1
While NOTCH2 loss-of-function is a supported disease mechanism (Alagille syndrome, via NOTCH2-related disorders), missense variants have also been reported as pathogenic in Alagille syndrome.
BP2
No observation in trans with a pathogenic variant in a dominant disorder or in cis with a pathogenic variant in a recessive disorder is available.
BP5
No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6
No reputable source has reported this variant as benign.
N/A · 3
PM5 · 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.567. BayesDel score = -0.0446258.
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. NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination.
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.
Sources & reference links