CDKN2Ac.183G>AUncertain significance

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Variant interpretation report

CDKN2A c.183G>A, p.(Glu61=)

NM_000077.5:c.183G>A NP_000068.1:p.(Glu61=) 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 CDKN2A

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 moderate (pathogenic)
Expert rules: Not recorded

Evidence considered

View criteria

Applied evidence criteria

PM2 (moderate): This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% rarity threshold and supports rarity in population databases.
BP7 (supporting): This variant is a synonymous substitution, p.(Glu61=), with no predicted effect on the protein sequence, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. These findings support a silent change without evidence of splice disruption.

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

PM2Moderate

PM2 · moderate

This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% rarity threshold and supports rarity in population databases.

Benign criteria applied · 1

BP7Supporting

BP7 · supporting

This variant is a synonymous substitution, p.(Glu61=), with no predicted effect on the protein sequence, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. These findings support a silent change without evidence of splice disruption.

Recorded classification: Uncertain significance

Generic ACMG/AMP 2015 final-classification combination rules were used as the applicable fallback framework because no usable official VCEP/CSPEC or local custom gene-specific final-classification framework was present.

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

0 / 1,596,036 alleles

gnomAD v4.1: 0 / 1,596,036 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP7 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 3 not met · 14 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The CDKN2A c.183G>A (p.Glu61=) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% PM2 rarity threshold.

In silico data support a silent variant without splice effect: the protein consequence is p.(Glu61=), SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and REVEL is 0.083.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1 and observed at 0/1,596,036 alleles in gnomAD v4.1 (AF 0.00000%), which is below the 0.1% rarity threshold and supports rarity in population databases. Details ▾Hide ▴

Rule

PM2

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: 0/1596036 alleles, AF 0.0, homozygotes 0

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP7 SupportingThis variant is a synonymous substitution, p.(Glu61=), with no predicted effect on the protein sequence, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. These findings support a silent change without evidence of splice disruption. Details ▾Hide ▴

Rule

BP7

Evidence considered

Protein consequence is p.(Glu61=)
SpliceAI DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; max delta score 0.00

Still missing

RNA studies could further confirm absence of splice effect

Sources

prefetchspliceai ↗

Not met · 3 · evaluated, threshold not reached

PM1 Available evidence does not support location in a mutational hotspot or other well-established critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴

Rule

PM1

Evidence considered

Cancer Hotspots: no hotspot row found
Evidence sentence states the variant does not lie in a statistically significant hotspot

Sources

hotspots ↗

BA1 Population frequency does not meet the standalone benign threshold. In gnomAD v4.1 the allele frequency is 0.00000% (0/1,596,036 alleles), which is below the 1% BA1 threshold. Details ▾Hide ▴

Rule

BA1

Evidence considered

gnomAD v4.1 AF 0.0, 0/1596036 alleles

Sources

gnomad_v4 ↗

BS1 Population frequency does not exceed the strong benign threshold. In gnomAD v4.1 the allele frequency is 0.00000% (0/1,596,036 alleles), which is below the 0.3% BS1 threshold. Details ▾Hide ▴

Rule

BS1

Evidence considered

gnomAD v4.1 AF 0.0, 0/1596036 alleles

Sources

gnomad_v4 ↗

Not assessed · 14 · no assessment recorded

PS2 No confirmed de novo data with verified maternity and paternity were identified for this variant. Details ▾Hide ▴

Rule

PS2

Evidence considered

No published case data were retrieved

Still missing

Proband-specific de novo testing data

Sources

literature_pass

PS3 No well-established functional studies showing a damaging effect on CDKN2A function or splicing were identified for this variant. Details ▾Hide ▴

Rule

PS3

Evidence considered

No variant-specific publications were identified
No experimental functional evidence was retrieved

Still missing

Validated functional or RNA studies specific to c.183G>A

Sources

literature_passspliceai ↗

PS4 No evidence was identified showing this variant is enriched in affected individuals compared with controls. Details ▾Hide ▴

Rule

PS4

Evidence considered

Variant absent from ClinVar
No published case evidence was retrieved

Still missing

Case series or case-control data

Sources

clinvar ↗literature_pass

PM3 No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴

Rule

PM3

Evidence considered

No published case data were retrieved

Still missing

Phase data and recessive case observations

Sources

literature_pass

PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴

Rule

PM6

Evidence considered

No published case data were retrieved

Still missing

De novo occurrence data

Sources

literature_pass

PP1 No segregation data were identified to show that this variant tracks with disease in affected family members. Details ▾Hide ▴

Rule

PP1

Evidence considered

No published family data were retrieved

Still missing

Family segregation studies

Sources

literature_pass

PP4 No phenotype or family-history information was provided to determine whether the clinical presentation is highly specific for a CDKN2A-related disorder. Details ▾Hide ▴

Rule

PP4

Still missing

Detailed phenotype and family history

PP5 No reputable source classification supporting pathogenicity was identified for this variant. Details ▾Hide ▴

Rule

PP5

Evidence considered

Variant absent from ClinVar

Still missing

Independent reputable pathogenic assertion

Sources

clinvar ↗

BS2 No evidence was identified showing this variant in healthy adults at a frequency inconsistent with disease penetrance. Details ▾Hide ▴

Rule

BS2

Still missing

Observation data in unaffected adults

BS3 No well-established functional studies demonstrating no damaging effect were identified for this variant. Details ▾Hide ▴

Rule

BS3

Evidence considered

No variant-specific publications were identified

Still missing

Validated benign functional or RNA studies

Sources

literature_pass

BS4 No family data were identified to show lack of segregation with disease. Details ▾Hide ▴

Rule

BS4

Evidence considered

No published family data were retrieved

Still missing

Family segregation studies

Sources

literature_pass

BP2 No phase data were identified to show this variant occurs in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴

Rule

BP2

Evidence considered

No published phase data were retrieved

Still missing

Allelic phase data

Sources

literature_pass

BP5 No evidence was identified that the reported phenotype is explained by an alternate molecular cause independent of this variant. Details ▾Hide ▴

Rule

BP5

Still missing

Comprehensive phenotype and alternative diagnosis data

BP6 No reputable source classification supporting a benign interpretation was identified for this variant. Details ▾Hide ▴

Rule

BP6

Evidence considered

Variant absent from ClinVar

Still missing

Independent reputable benign assertion

Sources

clinvar ↗

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis variant is a synonymous change, p.(Glu61=), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice-site variants. Although CDKN2A loss of function is an established germline disease mechanism, available evidence does not support applying PVS1 to this specific variant. Details ▾Hide ▴

Rule

PVS1

Evidence considered

CDKN2A loss of function is supported as a germline disease mechanism
Generic PVS1 scaffold states this variant does not qualify for default PVS1 null-variant buckets
Protein consequence is NP_000068.1:p.(Glu61=)

Sources

pvs1_gene_contextpvs1_variant_assessmentprefetchPMID:41673532 ↗PMID:36041817 ↗PMID:39820556 ↗PMID:40340749 ↗PMID:41118024 ↗

PS1 N/AThis variant does not alter the amino acid sequence and therefore does not meet the requirement for the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴

Rule

PS1

Evidence considered

Protein consequence is p.(Glu61=)
No ClinVar record was identified

Sources

prefetchclinvar ↗

PM4 N/AThis variant is a synonymous substitution and does not change protein length or create an in-frame deletion or insertion. Details ▾Hide ▴

Rule

PM4

Evidence considered

Protein consequence is p.(Glu61=)

Sources

prefetch

PM5 N/AThis criterion applies to a novel missense change at a residue with a different established pathogenic missense change. This variant is synonymous and does not create a missense substitution. Details ▾Hide ▴

Rule

PM5

Evidence considered

Protein consequence is p.(Glu61=)

Sources

prefetch

PP2 N/AThis criterion is intended for missense variants in genes where missense variation is a common disease mechanism. This variant is synonymous. Details ▾Hide ▴

Rule

PP2

Evidence considered

Protein consequence is p.(Glu61=)

Sources

prefetch

PP3 N/AThis variant is synonymous and available computational data do not predict a deleterious effect. SpliceAI shows a maximum delta score of 0.00, arguing against a splice impact. Details ▾Hide ▴

Rule

PP3

Evidence considered

Protein consequence is p.(Glu61=)
SpliceAI max delta score 0.00

Sources

spliceai ↗prefetch

BP1 N/AThis criterion applies to missense variants. This variant is synonymous. Details ▾Hide ▴

Rule

BP1

Evidence considered

Protein consequence is p.(Glu61=)

Sources

prefetch

BP3 N/AThis criterion applies to in-frame deletions or insertions in repetitive regions. This variant is a synonymous single-nucleotide substitution. Details ▾Hide ▴

Rule

BP3

Evidence considered

Variant is a single-nucleotide synonymous substitution

Sources

prefetch

BP4 N/AFor this synonymous variant, splice prediction is more appropriately considered under BP7 rather than BP4. Available computational data do not indicate a splice-disrupting effect. Details ▾Hide ▴

Rule

BP4

Evidence considered

SpliceAI max delta score 0.00
Protein consequence is p.(Glu61=)

Sources

spliceai ↗prefetch

Identifiers

Gene: CDKN2A
Transcript: NM_000077.5
Coding (HGVS c.): NM_000077.5:c.183G>A
Protein (HGVS p.): NP_000068.1:p.(Glu61=)
GRCh38: chr9:21971176 C>T
GRCh37: chr9:21971175 C>T

Gene diagram

Every interpreted variant in CDKN2A, mapped onto the exon structure of NM_000077.5. Select a row to find it on the plot.

CDKN2ANM_000077.5

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 0 / 1,596,036 alleles AF 0 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,596,036 alleles · 0 hom

No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1596036 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74908 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

BP7

Evidence considered

Protein consequence is p.(Glu61=)
SpliceAI DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; max delta score 0.00

Still missing

RNA studies could further confirm absence of splice effect

Sources

prefetchspliceai ↗

Rule

PP3

Evidence considered

Protein consequence is p.(Glu61=)
SpliceAI max delta score 0.00

Sources

spliceai ↗prefetch

Rule

BP4

Evidence considered

SpliceAI max delta score 0.00
Protein consequence is p.(Glu61=)

Sources

spliceai ↗prefetch

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 0 / 1,596,036 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record 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

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

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.