About CDKN2A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDKN2A c.226del, p.(Ala76ProfsTer70)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Strong
PVS1 · strong
Frameshift variant NM_001195132.1:c.226del (p.Ala76ProfsTer70) in CDKN2A exon 2 of 4 introduces a premature termination codon at position 145. CDKN2A loss of function is an established mechanism in familial melanoma. The PTC lies approximately 24 bp upstream of the exon 2–3 junction (c.457), raising possibility of NMD escape; under PMC6185798 this warrants PVS1 at strong rather than very strong. The truncated protein loses ankyrin repeats II–IV and the CDK4/CDK6 binding domain.
PM1Moderate
PM1 · moderate
The frameshift at codon 76 removes amino acids 76–168, deleting ankyrin repeats II–IV and the CDK4/CDK6 binding domain. Two independent publications demonstrate this region is critical for p16INK4a function: PMID:8603820 shows the core region 73–131 is necessary for CDK4 inhibition; PMID:8668202 shows truncation mutants in this region (e.g., R80ter) abolish CDK4/CDK6 binding and kinase inhibition.
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Allele frequency is below the 0.1% PM2 threshold in all population databases.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM1 moderate, PM2 moderate; combination = 1 strong + 2 moderate, which maps to Likely Pathogenic.
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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
28 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001195132.1:c.226del (p.Ala76ProfsTer70) is a frameshift variant in CDKN2A that introduces a premature termination codon at position 145, removing ankyrin repeats II–IV and the CDK4/CDK6 binding domain. CDKN2A loss of function is an established mechanism in familial melanoma.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele frequency of 0% across all population databases, well below the PM2 threshold of 0.1%.
The truncated protein loses the CDK4/CDK6 binding domain and ankyrin repeats II–IV. Two independent functional studies demonstrate this region is critical for p16INK4a tumor suppressor activity: the core region 73–131 is necessary for CDK4 inhibition, and premature termination mutants in this region abolish CDK4/CDK6 binding.
No variant-specific functional studies, segregation data, de novo observations, or clinical case reports were identified for this exact variant in the reviewed literature.
Under generic ACMG/AMP 2015 combination rules: PVS1 (strong) + PM1 (moderate) + PM2 (moderate) = Likely Pathogenic (1 strong + 2 moderate).
No criteria match.
Met · 3
PVS1 StrongFrameshift variant NM_001195132.1:c.226del (p.Ala76ProfsTer70) in CDKN2A exon 2 of 4 introduces a premature termination codon at position 145. CDKN2A loss of function is an established mechanism in familial melanoma. The PTC lies approximately 24 bp upstream of the exon 2–3 junction (c.457), raising possibility of NMD escape; under PMC6185798 this warrants PVS1 at strong rather than very strong. The truncated protein loses ankyrin repeats II–IV and the CDK4/CDK6 binding domain. Details ▾Hide ▴
Evidence considered
- Frameshift variant c.226del (p.Ala76ProfsTer70) in CDKN2A exon 2 of 4
- PTC at codon 145
- ~24 bp upstream of last exon–exon junction (c.457) — NMD may not occur
- CDKN2A germline loss of function established in familial melanoma (PMC6185798 framework eligible)
Still missing
- Confirm that NM_001195132.1 is the biologically relevant transcript for the clinical indication
Sources
PM1 ModerateThe frameshift at codon 76 removes amino acids 76–168, deleting ankyrin repeats II–IV and the CDK4/CDK6 binding domain. Two independent publications demonstrate this region is critical for p16INK4a function: PMID:8603820 shows the core region 73–131 is necessary for CDK4 inhibition; PMID:8668202 shows truncation mutants in this region (e.g., R80ter) abolish CDK4/CDK6 binding and kinase inhibition. Details ▾Hide ▴
Evidence considered
- Variant removes ankyrin repeats II–IV and the CDK4/CDK6 binding domain (aa 76–168 deleted)
- PMID:8603820: core region 73–131 necessary for CDK4 inhibition — deletion of N-terminal 65 aa abolishes function
- PMID:8668202: truncation mutant R80ter abolishes CDK4/CDK6 binding
- premature termination mutants upstream of aa 137 lose function
Sources
PM2 ModerateThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). Allele frequency is below the 0.1% PM2 threshold in all population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0)
- Absent from gnomAD v4.1 (AF = 0)
- Absent from gnomAD-Canada v1.0 (AF = 0)
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo observation with confirmed paternity and maternity has been reported for this variant in any reviewed source. Details ▾Hide ▴
Still missing
- No parental testing data available
PS3 No variant-specific functional data exist for c.226del. PMID:8603820 tested large deletion constructs (9-72, 9-131, 73-131, 73-156) and PMID:8668202 tested eight truncation mutants, but neither study directly assayed p.Ala76ProfsTer70. Domain-level inference from sparse testing does not satisfy PS3 under the governing calibration; this evidence is assigned to PM1. Details ▾Hide ▴
Evidence considered
- PMID:8603820: deletion constructs show core region 73-131 is critical for CDK4 inhibition — domain-level only
- PMID:8668202: truncation mutant R80ter abolishes CDK4/6 binding — domain-level only
Still missing
- No direct functional assay of c.226del or systematic tiling/saturation mutagenesis covering codon 76
Sources
PS4 No case-control association data or statistically significant enrichment in affected individuals has been reported for this variant. PMID:22703879 screened 572 individuals but the abstract does not confirm observation of c.226del; the ClinVar record citing this PMID corresponds to a different variant (NM_000077.5:c.150+76del, intronic). Details ▾Hide ▴
Still missing
- No variant-specific case counts or odds ratio data available
PM6 No de novo observation (with or without confirmed paternity/maternity) has been reported for this variant in any reviewed source. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No co-segregation data with disease in families has been reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
PP3 SpliceAI delta score is 0.00, indicating no predicted splice impact. REVEL and BayesDel scores are unavailable (not an SNV). No in silico evidence supports a pathogenic effect; however, the variant's pathogenicity is through protein truncation, not splicing, so computational splice predictions are not informative for this variant class. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- REVEL/BayesDel not applicable (indel
- not SNV)
Sources
PP4 No patient-specific phenotype data or clinical information has been provided to assess whether the clinical presentation is consistent with CDKN2A-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype data available
PP5 No reputable source (expert panel, clinical diagnostic laboratory) has classified this variant as pathogenic. ClinVar contains no exact match for this variant. The OncoKB classification of 'Likely Oncogenic' is a somatic cancer annotation and does not constitute germline PP5 evidence. Details ▾Hide ▴
No further detail was recorded.
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0)
- Absent from gnomAD v4.1 (AF = 0)
- Absent from gnomAD-Canada v1.0 (AF = 0)
Sources
BS1 This variant is absent from all population databases. Allele frequency of 0% is below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
BS2 No observation in healthy adult controls has been reported for this variant. Details ▾Hide ▴
Still missing
- No control population screening data available
BS3 No functional studies demonstrating a benign effect for this variant exist. The functional studies reviewed (PMID:8603820, PMID:8668202) demonstrate loss of function for truncating mutations in this region, consistent with a damaging effect, not a benign one. Details ▾Hide ▴
Evidence considered
- PMID:8603820: truncating deletions in the 73-131 region abolish CDK4 inhibition
- PMID:8668202: premature termination mutants upstream of aa 137 lose CDK4/CDK6 binding
Sources
BS4 No non-segregation data in families has been reported for this variant. Details ▾Hide ▴
Still missing
- No family co-segregation data available
BP2 No observation in trans with a known pathogenic variant has been reported for this variant. Details ▾Hide ▴
Still missing
- No phase data available
BP4 No multiple lines of benign computational evidence exist. SpliceAI delta is 0.00 (no splice impact), but this is a protein-truncating frameshift variant; the absence of a predicted splice effect does not constitute independent benign evidence for a variant whose pathogenicity is mediated through protein truncation. REVEL/BayesDel are not applicable to indels. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no splice impact
- but not informative for frameshift pathogenicity
Sources
BP5 No alternative molecular basis for disease has been identified to suggest this variant is incidental. Details ▾Hide ▴
Still missing
- No alternative molecular diagnosis data available
BP6 No reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
No further detail was recorded.
PS5 No reputable source (expert panel, clinical diagnostic laboratory) has classified this variant as pathogenic. The sole ClinVar submission (SCV000043253, Biesecker Lab) is a non-exact match for a different variant and reports Uncertain Significance with no assertion criteria. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a single-nucleotide deletion, not a nucleotide substitution at the same position. No known pathogenic SNV exists at c.226 for comparison. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a frameshift variant, not an in-frame deletion/insertion or stop-loss variant. PM4 applies only to non-frameshift protein length changes. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThis is a frameshift variant, not a missense change at a codon where a different missense is known to be pathogenic. PM5 candidate harvesting confirmed no same-residue missense comparators. Details ▾Hide ▴
No further detail was recorded.
PP2 N/AThis is a frameshift variant. PP2 applies specifically to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AThis is a frameshift variant. BP1 applies specifically to missense variants in genes where the primary disease mechanism is truncating. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AThis is a frameshift variant, not an in-frame deletion in a repetitive region. BP3 applies to in-frame deletions/insertions in repetitive or non-conserved regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a frameshift deletion, not a synonymous variant with no predicted splice impact. BP7 applies to synonymous and intronic variants. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CDKN2A
- Transcript
- NM_001195132.1
- Coding (HGVS c.)
- NM_001195132.1:c.226del
- Protein (HGVS p.)
- NP_001182061.1:p.(Ala76ProfsTer70)
- GRCh38
- chr9:21971132 GC>G
- GRCh37
- chr9:21971131 GC>G
- ClinVar
- 41574, 1789081
Gene diagram
Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_001195132.1. Select a row to find it on the plot.
CDKN2ANM_001195132.1
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 CDKN2A
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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
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI delta score is 0.00, indicating no predicted splice impact. REVEL and BayesDel scores are unavailable (not an SNV). No in silico evidence supports a pathogenic effect; however, the variant's pathogenicity is through protein truncation, not splicing, so computational splice predictions are not informative for this variant class. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no predicted splice impact
- REVEL/BayesDel not applicable (indel
- not SNV)
Sources
BP4 No multiple lines of benign computational evidence exist. SpliceAI delta is 0.00 (no splice impact), but this is a protein-truncating frameshift variant; the absence of a predicted splice effect does not constitute independent benign evidence for a variant whose pathogenicity is mediated through protein truncation. REVEL/BayesDel are not applicable to indels. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 — no splice impact
- but not informative for frameshift pathogenicity
Sources
BP7 N/AThis is a frameshift deletion, not a synonymous variant with no predicted splice impact. BP7 applies to synonymous and intronic variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
3 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 8603820 ↗Cancer-associated mis-sense and deletion mutations impair p16INK4 CDK inhibitory activity.Tests deletion constructs of p16INK4 (aa 9-72, 9-131, 73-131, 73-156) and missense mutant Arg87Pro via in vitro cyclin D1/CDK4 kinase inhibition and CDK4 binding assays. Demonstrates that the core region 73–131 is necessary but not sufficient for CDK4 inhibition; the N-terminus is also required. Concludes that nonsense mutations upstream of codon 131 are likely to impair or abolish p16INK4 inhibitory function. The specific variant c.226del (p.A76Pfs*70) was not tested or mentioned.→ PM1 Does not name this variant
Source detail
the core region (73-131) with sequences N-terminal to amino acid 73 of the p16INK4 molecule is necessary for its inhibitory function on CDK4
Location Full text reviewed; variant not found. Results (Fig 2b): deletion constructs 73-131 and 73-156 abolished CDK4 inhibition.
Context In vitro cyclin D1/CDK4 kinase inhibition assay using GST-p16INK4 fusion proteins expressed in E. coli; CDK4 binding assay with Sf9 insect cell lysates
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PMID 8668202 ↗Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma.Tests eight premature termination mutants (R58ter, R80ter, W110ter, E120ter, etc.), eight missense mutants (including R87P, G101W, V126D), and three N-terminal isoforms of p16CDKN2 via CDK4/CDK6 binding, kinase inhibition, and cell cycle arrest assays. Demonstrates that all premature termination mutants except D153ter lose CDK4/CDK6 binding. R80ter (nearest tested truncation to codon 76) abolishes function. G101W and V126D display temperature-sensitive loss of function. The specific variant c.226del was not among the tested alleles.→ PM1 Does not name this variant
Source detail
All the other truncations resulted in loss of binding, including W110ter and E120ter, which retain three complete ankyrin repeats
Location Full text reviewed; variant not found. Results (Fig 2): truncation mutants including R80ter abolished CDK4/CDK6 binding.
Context In vitro CDK4/CDK6 binding assay with 35S-labeled proteins; cyclin D2-Cdk4 kinase inhibition assay in Sf9 insect cells; G1 arrest assay in U2-OS osteosarcoma cells
Other recorded publications
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PMID 22703879 ↗Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.Johnston JJ et al. · 2012Screens 572 individuals undergoing exome sequencing for secondary variants in cancer-susceptibility genes. The ClinVar submission citing this PMID corresponds to NM_000077.5:c.150+76del (intronic), a different variant. The abstract does not mention NM_001195132.1:c.226del or p.Ala76ProfsTer70.Does not name this variant
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 0.000
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_001195132.1%3Ac.226del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-21971131-GC-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-21971132-GC-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-21971132-GC-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001195132.1%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/CDKN2A/A76Pfs*70
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDKN2A+c.226del
- 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
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.