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NOTCH2c.3570G>CUncertain significance
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Variant interpretation report

NOTCH2 c.3570G>C, p.(Glu1190Asp)

NM_024408.3:c.3570G>C NP_077719.2:p.(Glu1190Asp) 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 NOTCH2

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
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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).

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 supporting, BP4 supporting benign; combination = 1 supporting + 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
0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. 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. NOTCH2 encodes a transmembrane receptor that regulates many aspects of development by affecting cell-fate determination.

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.

27 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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).

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.

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.

This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes + genomes).
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.045 (predicted benign).
  • SpliceAI max delta: 0.07 (no splicing impact).
  • REVEL: 0.567 (borderline
  • outweighed by benign signals from BayesDel and SpliceAI).
Still missing
  • REVEL score is borderline (0.567)
  • confidence would be strengthened by additional benign in silico predictors.
Sources
bayesdelspliceai ↗revel

Not met · 22 · evaluated, threshold not reached

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). The generic PVS1 decision framework from PMC6185798 does not apply. Details ▾Hide ▴
Evidence considered
  • Missense substitution c.3570G>C predicted to cause p.Glu1190Asp
  • variant does not qualify as a predicted null variant under PVS1 criteria.
Sources
pvs1_generic_framework ↗
PS1 No previously established pathogenic variant at residue 1190 with the same amino acid change (p.Glu1190Asp) was identified. This variant is absent from ClinVar, and no literature reports an identical change at this position. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic comparator with same amino acid change found.
Sources
clinvar ↗
PS2 No de novo observation with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data found in any reviewed source.
Still missing
  • No trio or family-based sequencing data available.
PS3 No well-established in vitro or in vivo functional studies were identified for this variant. OncoKB reports no variant-specific reviewed functional evidence (classification: Unknown Oncogenic Effect). Details ▾Hide ▴
Evidence considered
  • OncoKB reports no variant-specific functional evidence
  • no publications describing functional characterization of p.Glu1190Asp found.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals is available. Details ▾Hide ▴
Evidence considered
  • No case-control or prevalence data found for this variant in any reviewed source.
Still missing
  • No affected-individual observations available.
PM1 Residue 1190 does not fall within a statistically significant mutational hotspot (CancerHotspots negative). No gene-specific VCEP/ClinGen domain specification is available for NOTCH2 to support a critical functional domain assignment at this position. Details ▾Hide ▴
Evidence considered
  • CancerHotspots analysis shows residue 1190 is not in a statistically significant hotspot
  • no VCEP domain specification available.
Still missing
  • No NOTCH2-specific functional domain specification from ClinGen or VCEP available.
PM6 No de novo observation (without confirmation of paternity and maternity) is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data found.
Still missing
  • No de novo reports available.
PP1 No cosegregation data in affected families is available for this variant. Details ▾Hide ▴
Evidence considered
  • No family-based cosegregation data found.
Still missing
  • No family data available.
PP2 NOTCH2 missense constraint data are not available (HCI prior not found). Without evidence that NOTCH2 has a low rate of benign missense variation and that missense is a common disease mechanism, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI prior scores unavailable for this variant
  • insufficient constraint evidence to apply PP2.
Still missing
  • NOTCH2 missense constraint metric (e.g.
  • Z-score
  • gnomAD missense o/e) not available.
PP3 In silico predictions are discordant. REVEL score 0.567 is marginally above the 0.5 threshold, but BayesDel score -0.045 is below 0 (predicted benign), and SpliceAI max delta 0.07 indicates no splicing impact. Multiple lines do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.567 (weakly damaging).
  • BayesDel: -0.045 (predicted benign).
  • SpliceAI max delta: 0.07 (no splicing impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or family history data are available; the variant was assessed as a standalone laboratory finding. Details ▾Hide ▴
Evidence considered
  • No proband phenotype or clinical data available.
Still missing
  • No clinical context provided for this case.
PP5 No reputable source has reported this variant as pathogenic; it is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
BA1 NM_024408.3:c.3570G>C is absent from all population databases. Allele frequency is 0.00%, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all population databases. Allele frequency is 0.00%, below the 0.3% BS1 threshold (non-VCEP). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • v4.1
  • and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No homozygous or hemizygous observations in healthy adults, and no trans observation with a known pathogenic variant, are available. Details ▾Hide ▴
Evidence considered
  • No homozygote or trans data available.
Still missing
  • No adult healthy cohort data for this variant.
BS3 No well-established functional studies showing no damaging effect are available for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies available.
Still missing
  • No functional data available.
BS4 No segregation data showing lack of cosegregation with disease is available. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No family data 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. The disease mechanism is not exclusively truncating, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
  • NOTCH2 LOF mechanism supported
  • but missense variants are also pathogenic in Alagille syndrome (GeneReviews / PMID:20301450).
Sources
pvs1_gene_context
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. Details ▾Hide ▴
Evidence considered
  • No cis or trans data available.
BP5 No observation of this variant in a case with an alternate molecular basis for disease is available. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis data found.
BP6 No reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar with no submitter classifications. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source classification available.
Sources
clinvar ↗
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/ANo same-residue comparator variants with established pathogenicity were identified. PM5 candidate harvesting was not possible, and no pathogenic variant at residue 1190 with a different amino acid change was found. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator identified.
BP3 N/AVariant is not an in-frame indel in a repetitive region. Details ▾Hide ▴
Evidence considered
  • Not applicable — substitution variant.
BP7 N/Ac.3570G>C is a missense variant (p.Glu1190Asp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Identifiers

Gene
NOTCH2
Transcript
NM_024408.3
Coding (HGVS c.)
NM_024408.3:c.3570G>C
Protein (HGVS p.)
NP_077719.2:p.(Glu1190Asp)
GRCh38
chr1:119935557 C>G
GRCh37
chr1:120478180 C>G

Gene diagram

Every interpreted variant in NOTCH2, mapped onto the exon structure of NM_024408.3. Select a row to find it on the plot.

NOTCH2NM_024408.3
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 -85 bp
0.000
SpliceAI acceptor gainat +47 bp
0.060
SpliceAI donor lossat +47 bp
0.000
SpliceAI donor gainat -85 bp
0.070
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.030

Other predictors

REVEL
0.567
BayesDel
-0.045

How the predictions were used

BP4 SupportingMultiple 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). Details ▾Hide ▴
Evidence considered
  • BayesDel: -0.045 (predicted benign).
  • SpliceAI max delta: 0.07 (no splicing impact).
  • REVEL: 0.567 (borderline
  • outweighed by benign signals from BayesDel and SpliceAI).
Still missing
  • REVEL score is borderline (0.567)
  • confidence would be strengthened by additional benign in silico predictors.
Sources
bayesdelspliceai ↗revel
PP3 In silico predictions are discordant. REVEL score 0.567 is marginally above the 0.5 threshold, but BayesDel score -0.045 is below 0 (predicted benign), and SpliceAI max delta 0.07 indicates no splicing impact. Multiple lines do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.567 (weakly damaging).
  • BayesDel: -0.045 (predicted benign).
  • SpliceAI max delta: 0.07 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/Ac.3570G>C is a missense variant (p.Glu1190Asp), not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.567. BayesDel score = -0.0446258.

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 0.070 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 = 0.07). REVEL score = 0.567. BayesDel score = -0.0446258.

Functional

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.

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.