About CCNE1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CCNE1 c.254G>A, p.(Arg85Gln)
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
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=6.36×10⁻⁵ (16/251,482 alleles), gnomAD v4.1 AF=4.03×10⁻⁵ (65/1,614,002 alleles), gnomAD-Canada AF=1.09×10⁻⁴ (2/18,412 alleles). Global allele frequency and grpmax FAF (0.000389) are well below the 0.1% PM2 threshold. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign interpretation. REVEL score 0.031 is strongly in the benign range (threshold >0.5 for pathogenic), BayesDel score -0.586 is negative (predicts benign), and SpliceAI max delta score is 0.00 (no predicted splicing impact). These concordant predictions suggest the variant has no deleterious effect on the gene product.
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; 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
65 / 1,614,002 alleles
gnomAD v4.1: 65 / 1,614,002 alleles. Recorded AF 4.02726e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36228e-05; MAF= 0.00636%, 16/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000457277; MAF= 0.04573%, 14/30616 alleles, homozygotes = 0); grpmax FAF= 0.00027587.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010862480990658266, 2/18412 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
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. CCNE1, a regulator of the cell cycle, is amplified 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.
29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001238.4:c.254G>A (p.Arg85Gln) is a missense variant in CCNE1.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0064% (16/251,482 alleles), gnomAD v4.1 AF=0.0040% (65/1,614,002 alleles), with no homozygotes observed. The maximum subpopulation frequency is 0.051% in the South Asian population. These frequencies meet the PM2 threshold (<0.1%).
Multiple in silico prediction tools concordantly support a benign interpretation: REVEL score 0.031 (benign range), BayesDel score -0.586 (predicts benign), and SpliceAI max delta 0.00 (no predicted splicing impact). These findings meet the BP4 threshold (multiple lines of computational evidence suggest no impact).
This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics; criteria provided, single submitter). No expert panel review or pathogenic assertion is available.
No variant-specific functional studies, de novo observations, segregation data, or case-control evidence are available.
Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting) is balanced by BP4 (supporting). Neither a pathogenic combination (requiring ≥2 supporting or ≥1 moderate + ≥1 supporting) nor a benign/likely benign combination (requiring ≥2 supporting benign or ≥1 strong benign + ≥1 supporting benign) is satisfied.
Overall classification: Uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=6.36×10⁻⁵ (16/251,482 alleles), gnomAD v4.1 AF=4.03×10⁻⁵ (65/1,614,002 alleles), gnomAD-Canada AF=1.09×10⁻⁴ (2/18,412 alleles). Global allele frequency and grpmax FAF (0.000389) are well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 16/251
- 482 alleles (AF=0.0064%)
- 0 homozygotes
- gnomAD v4.1: 65/1
- 614
- 002 alleles (AF=0.0040%)
- gnomAD-Canada: 2/18
- 412 alleles (AF=0.0109%)
- Highest subpopulation AF: South Asian 0.051% (below 0.1% threshold)
Sources
BP4 SupportingMultiple lines of computational evidence support a benign interpretation. REVEL score 0.031 is strongly in the benign range (threshold >0.5 for pathogenic), BayesDel score -0.586 is negative (predicts benign), and SpliceAI max delta score is 0.00 (no predicted splicing impact). These concordant predictions suggest the variant has no deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.031 (benign range
- far below pathogenic threshold of 0.5)
- BayesDel: -0.586 (negative score
- predicts benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No established pathogenic variant causing the same amino acid change (p.Arg85Gln / R85Q) has been identified in ClinVar or the literature. The single ClinVar submission classifies this variant as Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar reports VUS (VCV003997617)
- no known pathogenic variant at Arg85.
Still missing
- No systematic same-residue pathogenic comparator search yielded results.
Sources
PS2 No de novo occurrence data are available for this variant. PS2 requires confirmation of both maternity and paternity in a de novo observation. Details ▾Hide ▴
Still missing
- No de novo or trio data available.
PS3 No well-established in vitro or in vivo functional studies demonstrating a deleterious effect of p.Arg85Gln have been identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies found.
Still missing
- No functional studies of p.Arg85Gln in any experimental system.
Sources
PS4 No case-control or cohort data demonstrating statistically increased prevalence of this variant in affected individuals versus controls are available. Details ▾Hide ▴
Still missing
- No affected-vs-control prevalence data available.
PM1 Residue 85 does not lie within a known mutational hotspot or a critical functional domain where pathogenic missense variants cluster and benign variation is absent. Systematic hotspot analysis found no statistically significant enrichment at this residue. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: residue_significant=false
- exact_variant_listed=no.
Still missing
- No domain-specific functional annotation for Arg85.
PM5 No pathogenic missense variant has been established at the same residue (Arg85). Automated PM5 candidate harvesting was unable to identify any same-residue comparator variants with pathogenic classification. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-residue pathogenic comparators found.
Still missing
- No ClinVar entries for other missense changes at Arg85.
Sources
pm5_candidates
PM6 No de novo observation of this variant has been reported. PM6 requires a de novo finding without confirmation of paternity and maternity. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No cosegregation data are available for this variant in affected families. Details ▾Hide ▴
Still missing
- No family cosegregation data.
PP2 CCNE1 is not established as a gene in which missense variants are a common mechanism of disease with a low rate of benign missense variation. No gene-level missense constraint metric supports PP2 application. Details ▾Hide ▴
Evidence considered
- CCNE1 is primarily an oncogene (amplifications in cancer)
- not a classic germline disease gene with established missense constraint.
Still missing
- No missense Z-score or constraint metric available for CCNE1.
PP3 Multiple in silico prediction tools support a benign interpretation: REVEL score 0.031 (strongly predicts benign; threshold >0.5 for pathogenic), BayesDel score -0.586 (negative, predicts benign), SpliceAI max delta 0.00 (no splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.031 (strongly benign
- well below pathogenic threshold of 0.5)
- BayesDel: -0.586 (negative score
- predicts benign)
- SpliceAI: max delta 0.00 (no predicted splice alteration)
Sources
PP4 No patient phenotype information is available to assess whether this variant occurs in a patient with a phenotype highly specific for CCNE1-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype data available.
PP5 No reputable source has reported this variant as pathogenic. The single ClinVar submission classifies it as Uncertain significance (Ambry Genetics, criteria provided single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- no source reports as pathogenic.
Sources
BA1 Global allele frequency (gnomAD v4.1: 0.0040%; v2.1: 0.0064%) is far below the 1% BA1 threshold. Maximum subpopulation frequency (South Asian: 0.051%) also remains well below 1%. Details ▾Hide ▴
Evidence considered
- Global AF: 0.0040-0.0064% (threshold >1%)
- Max subpopulation AF: 0.051% South Asian (threshold >1%)
Sources
BS1 Global allele frequency (0.0040-0.0064%) and maximum subpopulation frequency (South Asian: 0.051%) are below the 0.3% BS1 threshold. The variant is not common enough in population databases to support a benign interpretation via BS1. Details ▾Hide ▴
Evidence considered
- Global AF: 0.0040-0.0064% (threshold >0.3%)
- Max subpopulation AF: 0.051% South Asian (threshold >0.3%)
Sources
BS2 No specific observation of this variant in a healthy adult individual for a fully penetrant disorder has been documented. While gnomAD includes generally healthy individuals, BS2 requires explicit evidence of the variant in a healthy individual with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No individual-level phenotype data confirming healthy status of variant carriers.
BS3 No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of p.Arg85Gln have been identified. In silico predictions alone do not satisfy BS3. Details ▾Hide ▴
Still missing
- No functional assay data for p.Arg85Gln.
BS4 No segregation data demonstrating lack of segregation with disease are available. Details ▾Hide ▴
Still missing
- No family segregation data.
BP1 CCNE1 is not established as a gene in which only truncating (loss-of-function) variants cause disease. BP1 requires that the disease mechanism for the gene is exclusively through truncating variants, which has not been demonstrated for CCNE1. Details ▾Hide ▴
Evidence considered
- CCNE1 disease mechanism not established as exclusively truncating.
Still missing
- No established gene-disease relationship supporting truncating-only mechanism.
BP2 No observation of this variant in trans with a known pathogenic variant in CCNE1 has been reported. Details ▾Hide ▴
Still missing
- No trans phasing data available.
BP5 No case has been identified in which this variant is found in a patient with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No case-level data with alternate molecular diagnosis.
BP6 No reputable source has reported this variant as benign. The single ClinVar submission classifies it as Uncertain significance. Details ▾Hide ▴
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites). NM_001238.4:c.254G>A is a missense variant (p.Arg85Gln) and does not fall into any PVS1 null-variant bucket per the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution in exon 5
- variant_bucket='other'
- not a null variant.
Sources
PM3 N/APM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. This is a single heterozygous missense substitution without phasing data for a gene without established recessive inheritance. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions or stop-loss variants. This is a single-nucleotide missense substitution causing an amino acid change without altering protein length. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001238.4:c.254G>A is a missense variant (p.Arg85Gln), not synonymous. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 sequence variant interpretation framework (PMID:25741868). No VCEP-specific extension defines PS5 for this gene. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CCNE1
- Transcript
- NM_001238.4
- Coding (HGVS c.)
- NM_001238.4:c.254G>A
- Protein (HGVS p.)
- NP_001229.1:p.(Arg85Gln)
- GRCh38
- chr19:29817210 G>A
- GRCh37
- chr19:30308117 G>A
- ClinVar
- 3997617
Gene diagram
Every interpreted variant in CCNE1, mapped onto the exon structure of NM_001238.4. Select a row to find it on the plot.
CCNE1NM_001238.4
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 CCNE1
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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
65 / 1,614,002 alleles
AF 4.03e-05 · 0 homozygotes · FAF 0.000389
gnomAD v2.1
16 / 251,482 alleles
AF 6.36e-05 · 0 homozygotes · FAF 0.000276
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 4e-05 · 65 / 1,614,002 alleles · 0 hom · FAF 0.00039
| South Asian46 / 91,072 | 0.00051 |
| Admixed American1 / 59,994 | 1.7e-05 |
| Remaining individuals1 / 62,480 | 1.6e-05 |
| European (non-Finnish)17 / 1,180,042 | 1.4e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 6.4e-05 · 16 / 251,482 alleles · 0 hom · FAF 0.00028
| South Asian14 / 30,616 | 0.00046 |
| European (non-Finnish)2 / 113,758 | 1.8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.02726e-05; MAF= 0.00403%, 65/1614002 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000505095; MAF= 0.05051%, 46/91072 alleles, homozygotes = 0); grpmax FAF= 0.00038907.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36228e-05; MAF= 0.00636%, 16/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000457277; MAF= 0.04573%, 14/30616 alleles, homozygotes = 0); grpmax FAF= 0.00027587.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010862480990658266, 2/18412 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.031
- BayesDel
- -0.586
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign interpretation. REVEL score 0.031 is strongly in the benign range (threshold >0.5 for pathogenic), BayesDel score -0.586 is negative (predicts benign), and SpliceAI max delta score is 0.00 (no predicted splicing impact). These concordant predictions suggest the variant has no deleterious effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.031 (benign range
- far below pathogenic threshold of 0.5)
- BayesDel: -0.586 (negative score
- predicts benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
PP3 Multiple in silico prediction tools support a benign interpretation: REVEL score 0.031 (strongly predicts benign; threshold >0.5 for pathogenic), BayesDel score -0.586 (negative, predicts benign), SpliceAI max delta 0.00 (no splicing impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.031 (strongly benign
- well below pathogenic threshold of 0.5)
- BayesDel: -0.586 (negative score
- predicts benign)
- SpliceAI: max delta 0.00 (no predicted splice alteration)
Sources
BP7 N/ABP7 is reserved for synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_001238.4:c.254G>A is a missense variant (p.Arg85Gln), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.031. BayesDel score = -0.586426.
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
65 / 1,614,002 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
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/variation/3997617/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-30308117-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-29817210-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-29817210-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001238.4%3Ac.254G…
- OncoKB ↗www.oncokb.org/gene/CCNE1/R85Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CCNE1+c.254G%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
This variant is present in gnomAD v4.1 (AF= 4.02726e-05; MAF= 0.00403%, 65/1614002 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000505095; MAF= 0.05051%, 46/91072 alleles, homozygotes = 0); grpmax FAF= 0.00038907.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36228e-05; MAF= 0.00636%, 16/251482 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000457277; MAF= 0.04573%, 14/30616 alleles, homozygotes = 0); grpmax FAF= 0.00027587.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010862480990658266, 2/18412 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3997617)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.031. BayesDel score = -0.586426.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CCNE1, a regulator of the cell cycle, is amplified 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.