About CCND2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CCND2 c.389C>A, p.(Ser130Tyr)
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
Variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele count 0 across all datasets). Meets PM2 threshold of <0.1% for non-VCEP generic ACMG.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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 moderate; combination = 1 moderate, 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
0.000 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CCND2, 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: 1 met · 5 not met · 11 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001759.3:c.389C>A (p.Ser130Tyr) in CCND2 is absent from all population databases, meeting PM2 at moderate strength.
No other pathogenic or benign criteria were met. PVS1 is not applicable for this missense variant. All remaining criteria are either not met, not assessed due to absence of data, or not applicable to this variant type.
With a single moderate pathogenic criterion (PM2) and no supporting criteria, the variant does not reach likely pathogenic, likely benign, or benign thresholds per generic ACMG/AMP 2015 combination rules (PMID:25741868). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 ModerateVariant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele count 0 across all datasets). Meets PM2 threshold of <0.1% for non-VCEP generic ACMG. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: AC=0
- AF=0.0.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 Residue Ser130 is not located in a statistically significant mutational hotspot (Cancer Hotspots: not significant). No evidence that this position lies within a critical functional domain devoid of benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots analysis: residue not significant
- exact variant not listed.
Still missing
- No domain-specific constraint data or functional domain annotation for this residue.
PP3 Conflicting in silico predictions: REVEL score 0.585 (borderline, just above 0.5 threshold), BayesDel score 0.118 (low, not supporting pathogenicity), SpliceAI max delta 0.00 (no splice effect). Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.585
- BayesDel: 0.118
- SpliceAI: max delta 0.00.
Sources
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (AF=0). Does not meet the BA1 threshold of >1% allele frequency (non-VCEP generic ACMG). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: AF=0.0.
Sources
BS1 Variant is absent from all population databases (AF=0). Does not meet the BS1 threshold of >0.3% allele frequency (non-VCEP generic ACMG). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- gnomAD-Canada: AF=0.0.
Sources
BP4 In silico predictions do not support a benign interpretation. REVEL score 0.585 is above the benign range (<0.25). Evidence does not provide multiple lines of benign computational support. Details ▾Hide ▴
Evidence considered
- REVEL: 0.585 (not in benign range)
- BayesDel: 0.118
- SpliceAI: max delta 0.00.
Sources
Not assessed · 11 · no assessment recorded
PS2 No de novo data (with confirmed paternity and maternity) are available for this variant in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No family data or de novo reporting available.
PS3 No variant-specific functional studies identified. OncoKB reports 'Unknown Oncogenic Effect' with no curated functional evidence for this variant. No PMIDs with functional data were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
Still missing
- No functional assay data available for p.Ser130Tyr.
Sources
PS4 No case-control or cohort data available. Variant is absent from ClinVar with zero submissions, precluding any prevalence comparison. Details ▾Hide ▴
Evidence considered
- Zero ClinVar submissions
- no cohort data.
Still missing
- No affected vs. control prevalence data.
Sources
PM6 No de novo observation data available for this variant in ClinVar or literature; PM6 cannot be assessed without a de novo report. Details ▾Hide ▴
Still missing
- No de novo reporting for this variant.
PP1 No co-segregation data available. No family studies involving this variant have been reported. Details ▾Hide ▴
Still missing
- No segregation data available.
PP2 CCND2 is associated with MPPH syndrome where heterozygous missense variants are a known disease mechanism (GeneReviews, PMID:27854409). However, quantitative constraint metrics to establish a low rate of benign missense variation (HCI prior unavailable for CCND2; no missense Z-score) are absent, precluding confident application of PP2. Details ▾Hide ▴
Evidence considered
- GeneReviews (PMID:27854409): CCND2 is an MPPH causative gene via heterozygous pathogenic variants. HCI prior not available for CCND2.
Still missing
- HCI prior/missense constraint scores unavailable for CCND2
- cannot quantify benign missense variation rate.
PP4 No patient phenotype or clinical data are available; variant is not reported in ClinVar with associated phenotype information. Details ▾Hide ▴
Still missing
- No patient phenotype data available for specificity assessment.
BS3 No functional studies assessing this variant are available. OncoKB reports no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional data.
Still missing
- No functional assay data for p.Ser130Tyr.
Sources
BS4 No family segregation data available; no reports of non-segregation with disease phenotype. Details ▾Hide ▴
Still missing
- No segregation data.
BP2 No phase data available. No observations of this variant in trans or cis with another pathogenic variant. Details ▾Hide ▴
Still missing
- No phase information.
BP5 No data available regarding an alternate molecular basis for disease in any individual carrying this variant. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis data.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AVariant is a missense substitution (p.Ser130Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus); does not meet the generic PVS1 framework criteria per ClinGen SVI recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant in exon 2
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
PS1 N/ANo previously established pathogenic variant at amino acid position Ser130 has been reported in ClinVar or the literature; variant is entirely absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no comparator pathogenic variant at same residue.
Sources
PM3 N/ARecessive-disorder criterion; CCND2-associated MPPH syndrome is autosomal dominant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein-length change criterion; variant is a missense substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at the same amino acid residue (Ser130) was identified in ClinVar for comparison; PM5 candidate harvesting returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
- Zero same-residue comparator variants found in ClinVar.
Sources
clinvar ↗pm5_candidates
PP5 N/ANo reputable source (ClinVar, expert panel, or peer-reviewed publication) has classified this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- zero submissions
- no expert panel classification.
Sources
BS2 N/AVariant has not been observed in any individual in population databases or ClinVar; no observation in a healthy adult homozygous state is possible for an absent variant. Details ▾Hide ▴
Evidence considered
- Variant absent from all databases
- no observation in any individual.
BP1 N/ACCND2-associated MPPH syndrome is primarily caused by missense (gain-of-function) variants, not truncating variants. BP1 applies only when the gene's disease mechanism is primarily through truncating variants. Details ▾Hide ▴
Evidence considered
- GeneReviews (PMID:27854409): MPPH caused by heterozygous pathogenic variants in CCND2
- typically missense.
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame deletion or insertion. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo reputable source (ClinVar, expert panel, or peer-reviewed publication) has reported this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
BP7 N/AVariant is a missense change (c.389C>A, p.Ser130Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
PS5 N/APS5 is not part of the standard ACMG/AMP 2015 criteria framework (PMID:25741868). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CCND2
- Transcript
- NM_001759.3
- Coding (HGVS c.)
- NM_001759.3:c.389C>A
- Protein (HGVS p.)
- NP_001750.1:p.(Ser130Tyr)
- GRCh38
- chr12:4276198 C>A
- GRCh37
- chr12:4385364 C>A
Gene diagram
Every interpreted variant in CCND2, mapped onto the exon structure of NM_001759.3. Select a row to find it on the plot.
CCND2NM_001759.3
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 CCND2
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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
- 0.585
- BayesDel
- 0.118
How the predictions were used
PP3 Conflicting in silico predictions: REVEL score 0.585 (borderline, just above 0.5 threshold), BayesDel score 0.118 (low, not supporting pathogenicity), SpliceAI max delta 0.00 (no splice effect). Multiple lines of computational evidence do not converge on a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.585
- BayesDel: 0.118
- SpliceAI: max delta 0.00.
Sources
BP4 In silico predictions do not support a benign interpretation. REVEL score 0.585 is above the benign range (<0.25). Evidence does not provide multiple lines of benign computational support. Details ▾Hide ▴
Evidence considered
- REVEL: 0.585 (not in benign range)
- BayesDel: 0.118
- SpliceAI: max delta 0.00.
Sources
BP7 N/AVariant is a missense change (c.389C>A, p.Ser130Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.585. BayesDel score = 0.118406.
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 0.000
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_001759.3%3Ac.389C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-4385364-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-4276198-C-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-4276198-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001759.3%3Ac.389C…
- OncoKB ↗www.oncokb.org/gene/CCND2/S130Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CCND2+c.389C%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 = 0.00). REVEL score = 0.585. BayesDel score = 0.118406.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CCND2, 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.