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%).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).2 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.3 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.4 Overall classification: Uncertain significance.
CCNE1
Final classification
VUS
PM2BP4
CCNE1
c.254G>A
p.Arg85Gln
This variant
NM_001238.4:c.254G>A (p.Arg85Gln) is a missense variant in CCNE1.
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.
Classification rationale
PM2
BP4
VUS
CCNE1 c.254G>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001238.4 · variants mapped to exon structure
CCNE1
NM_001238.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
gnomAD v2.1: 16/251482 alleles (AF=0.0064%)0 homozygotes
✓
BP4
supporting
Benign
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.
REVEL: 0.031 (benign rangefar below pathogenic threshold of 0.5)BayesDel: -0.586 (negative score
Assessed · not applied
· 21 not met · 0 not assessed
Pathogenic
PS1
No established pathogenic variant causing the same amino acid change (p.Arg85Gln / R85Q) has been identified in ClinVar or the literature.
PS2
No de novo occurrence data are available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a deleterious effect of p.Arg85Gln have been identified.
PS4
No case-control or cohort data demonstrating statistically increased prevalence of this variant in affected individuals versus controls are 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.
PM5
No pathogenic missense variant has been established at the same residue (Arg85).
PM6
No de novo observation of this variant has been reported.
PP1
No cosegregation data are available for this variant in affected families.
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.
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).
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.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
Global allele frequency (gnomAD v4.1: 0.0040%; v2.1: 0.0064%) is far below the 1% BA1 threshold.
BS1
Global allele frequency (0.0040-0.0064%) and maximum subpopulation frequency (South Asian: 0.051%) are below the 0.3% BS1 threshold.
BS2
No specific observation of this variant in a healthy adult individual for a fully penetrant disorder has been documented.
BS3
No well-established in vitro or in vivo functional studies demonstrating no deleterious effect of p.Arg85Gln have been identified.
BS4
No segregation data demonstrating lack of segregation with disease are available.
BP1
CCNE1 is not established as a gene in which only truncating (loss-of-function) variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant in CCNE1 has been reported.
BP5
No case has been identified in which this variant is found in a patient with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00010862480990658266, 2/18412 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.004%
· 65 / 1,614,002
0 hom · FAF 0.039%
0 hom · FAF 0.039%
South Asian 46 / 91,072 |
0.051% |
Admixed American 1 / 59,994 |
0.0017% |
Remaining individuals 1 / 62,480 |
0.0016% |
European (non-Finnish) 17 / 1,180,042 |
0.0014% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0064%
· 16 / 251,482
0 hom · FAF 0.028%
0 hom · FAF 0.028%
South Asian 14 / 30,616 |
0.046% |
European (non-Finnish) 2 / 113,758 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
0.011%
· 2 / 18,412
0 hom · FAF 0.026%
0 hom · FAF 0.026%
South Asian 2 / 1,362 |
0.15% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links