About CDKN2B
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDKN2B c.125G>A, p.(Gly42Glu)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
The variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold for a rare variant in a gene where the variant has not been observed in large population cohorts.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence consistently predict a benign effect: REVEL score 0.067 (benign range), BayesDel score -0.40492 (benign range), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico tools concordantly support a benign interpretation.
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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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. CDKN2B, a tumor suppressor and cell cycle regulator, is inactivated by mutation or deletion in various cancer types.
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
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 · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The variant NM_004936.3:c.125G>A (p.Gly42Glu) in CDKN2B is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at supporting strength.
Multiple in silico predictors consistently indicate a benign effect: REVEL 0.067, BayesDel -0.40492, and SpliceAI max delta 0.01, meeting BP4 at supporting benign strength.
The variant has not been reported in ClinVar, COSMIC, or the published literature. No functional data, segregation data, case-control data, or de novo observations are available.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is equivocal. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting the PM2 threshold for a rare variant in a gene where the variant has not been observed in large population cohorts. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada v1.0: absent (AC=0)
Sources
BP4 SupportingMultiple lines of computational evidence consistently predict a benign effect: REVEL score 0.067 (benign range), BayesDel score -0.40492 (benign range), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico tools concordantly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign
- threshold >0.5 for pathogenic)
- BayesDel: -0.40492 (benign
- threshold >0 for pathogenic)
- SpliceAI: max delta 0.01 (no predicted splice alteration)
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No previously established pathogenic variant at the same amino acid position (Gly42) has been reported in ClinVar or the published literature, so PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no comparator at Gly42
Still missing
- No ClinVar entries for any variant at this codon
Sources
PS2 No parental or pedigree data are available to assess de novo occurrence of this variant. Details ▾Hide ▴
Still missing
- No pedigree or parental genotype data available
PS3 No functional experimental data exist for this variant or for a systematically characterized range that includes residue Gly42. OncoKB reports Unknown Oncogenic Effect. No variant-specific functional studies were identified in the literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific reviewed functional evidence
- Literature: zero PMIDs identified with variant-specific functional data
Still missing
- No functional assays performed for p.Gly42Glu or systematic characterization of the N-terminal region of CDKN2B
Sources
PS4 No case-control or cohort data comparing the prevalence of this variant in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
- No case-control studies available
PM1 The variant is not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional characterization data specific to the CDKN2B N-terminal region around residue Gly42 are available in the case evidence to support PM1 application. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue Gly42 is not significant
- No domain-level functional evidence for this region in the case materials
Still missing
- Domain-level functional characterization of early N-terminal CDKN2B not available in case evidence
PM6 No de novo data are available for this variant; PM6 cannot be applied without a reported de novo observation. Details ▾Hide ▴
Still missing
- No de novo reports identified in ClinVar or literature
PP1 No family segregation data are available to assess co-segregation of this variant with disease. Details ▾Hide ▴
Still missing
- No pedigree or co-segregation data available
PP2 Insufficient data to apply PP2. Missense constraint metrics (z-score, HCI prior) are not available for CDKN2B; the HCI prior lookup returned 'gene_not_supported'. It cannot be determined whether this gene has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported — no missense constraint data available
Still missing
- No missense constraint z-score or HCI prior score for CDKN2B
PP3 Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.067, BayesDel score -0.40492, and SpliceAI max delta 0.01. In silico evidence does not support a pathogenic role and instead supports benign through BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign range
- threshold >0.5 for pathogenic)
- BayesDel: -0.40492 (benign range)
- SpliceAI: max delta 0.01 (no predicted splice effect)
Sources
PP4 No patient phenotype or clinical information is available to assess whether the individual's presentation is specific for a CDKN2B-associated disorder. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
PP5 The variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: variant not found
Still missing
- Not reported by any clinical laboratory in ClinVar
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: AF = 0.0%
Sources
BS1 The variant is absent from all population databases. The allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF < 0.3%)
- gnomAD v4.1: absent (AF < 0.3%)
- gnomAD-Canada: AF = 0.0%
Sources
BS2 No data on healthy adult carriers are available to assess whether this variant is observed in individuals without disease for a fully penetrant disorder. Details ▾Hide ▴
Still missing
- No healthy carrier data available
BS3 No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing. In silico predictors alone are insufficient for BS3; they are captured under BP4. Details ▾Hide ▴
Evidence considered
- No experimental functional studies available for this variant
Still missing
- No functional characterization of p.Gly42Glu in CDKN2B
BS4 No segregation data are available to assess lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No pedigree or segregation data available
BP1 CDKN2B germline missense variants are a recognized disease mechanism. PMID:25873077 identified germline missense mutations in CDKN2B predisposing to renal cell carcinoma. BP1 applies only when truncating variants are the sole known mechanism, which is not the case for CDKN2B. Details ▾Hide ▴
Evidence considered
- CDKN2B germline missense mutations cause autosomal dominant renal cell carcinoma (PMID:25873077)
BP2 No data are available on whether this variant has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No trans configuration data available
BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data available
BP6 The variant is absent from ClinVar; no reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: variant not found
Still missing
- Not reported by any clinical laboratory in ClinVar
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.125G>A, p.Gly42Glu) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant class: substitution (missense
- p.Gly42Glu)
- PVS1 variant assessment: bucket = 'other'
- apply_generic_pvs1_framework = false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo same-residue (Gly42) comparator variants with pathogenic classification were identified in ClinVar. PM5 candidate harvesting was not possible for this variant. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-residue comparators found
Sources
pm5_candidates
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant (c.125G>A, p.Gly42Glu) is a missense substitution, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant class: missense (p.Gly42Glu)
- not synonymous
PS5 N/ACDKN2B is associated with autosomal dominant cancer predisposition (renal cell carcinoma); it is not a recessive disorder gene. PS5 applies only to recessive disorders where the variant is found in trans with a pathogenic variant. Details ▾Hide ▴
Evidence considered
- CDKN2B germline mutations cause autosomal dominant renal cell carcinoma predisposition
Identifiers
- Gene
- CDKN2B
- Transcript
- NM_004936.3
- Coding (HGVS c.)
- NM_004936.3:c.125G>A
- Protein (HGVS p.)
- NP_004927.2:p.(Gly42Glu)
- GRCh38
- chr9:22008829 C>T
- GRCh37
- chr9:22008828 C>T
Gene diagram
Every interpreted variant in CDKN2B, mapped onto the exon structure of NM_004936.3. Select a row to find it on the plot.
CDKN2BNM_004936.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDKN2B
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.067
- BayesDel
- -0.405
How the predictions were used
BP4 SupportingMultiple lines of computational evidence consistently predict a benign effect: REVEL score 0.067 (benign range), BayesDel score -0.40492 (benign range), and SpliceAI max delta score 0.01 (no predicted splicing impact). All three in silico tools concordantly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign
- threshold >0.5 for pathogenic)
- BayesDel: -0.40492 (benign
- threshold >0 for pathogenic)
- SpliceAI: max delta 0.01 (no predicted splice alteration)
Sources
PP3 Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.067, BayesDel score -0.40492, and SpliceAI max delta 0.01. In silico evidence does not support a pathogenic role and instead supports benign through BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.067 (benign range
- threshold >0.5 for pathogenic)
- BayesDel: -0.40492 (benign range)
- SpliceAI: max delta 0.01 (no predicted splice effect)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant (c.125G>A, p.Gly42Glu) is a missense substitution, not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant class: missense (p.Gly42Glu)
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.067. BayesDel score = -0.40492.
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 0.010
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004936.3%3Ac.125G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-22008828-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-22008829-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-22008829-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004936.3%3Ac.125G…
- OncoKB ↗www.oncokb.org/gene/CDKN2B/G42E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDKN2B+c.125G%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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 = 0.01). REVEL score = 0.067. BayesDel score = -0.40492.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDKN2B, a tumor suppressor and cell cycle regulator, is inactivated by mutation or deletion in various cancer types.
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.