About CREBBP
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CREBBP c.3215C>G, p.(Ser1072Cys)
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 absent from gnomAD v2.1 (exomes) and present at an extremely low frequency in gnomAD v4.1 (AF=6.19×10⁻⁷, 1/1,614,258 alleles, 0 homozygotes), well below the PM2 threshold of 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign impact: REVEL score 0.046 (well below pathogenic thresholds), BayesDel score -0.448 (predicted benign), and SpliceAI max delta 0.00 (no splice alteration predicted).
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 benign; 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
1 / 1,614,258 alleles
gnomAD v4.1: 1 / 1,614,258 alleles. Recorded AF 6.1948e-07. Recorded homozygote count 0.
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.
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. CREBBP, a tumor suppressor and transcriptional co-activator, is frequently inactivated in hematologic malignancies.
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.
26 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004380.2:c.3215C>G (p.Ser1072Cys) is a missense variant in CREBBP. It is absent from ClinVar and absent from gnomAD v2.1, with a single heterozygous observation in gnomAD v4.1 at extremely low frequency (AF=6.19×10⁻⁷, 1/1,614,258).
This low population frequency meets PM2 at supporting strength.
Multiple computational predictors support a benign impact: REVEL score 0.046 (benign-leaning), BayesDel score -0.448 (predicted benign), and SpliceAI predicts no splice alteration (max Δ=0.00). This meets BP4 at supporting benign strength.
No variant-specific functional data, de novo observations, segregation data, or published case reports are available. No same-codon pathogenic comparators exist for PM5 or PS1. The variant is not in a mutational hotspot or characterized functional domain.
The variant does not qualify for PVS1 (missense, not a null variant). BP1 does not apply because missense variants are an established disease mechanism in CREBBP.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification as pathogenic, likely pathogenic, likely benign, or benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and present at an extremely low frequency in gnomAD v4.1 (AF=6.19×10⁻⁷, 1/1,614,258 alleles, 0 homozygotes), well below the PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- single heterozygous observation in gnomAD v4.1 (1/1
- 614
- 258 alleles
- AF=6.19×10⁻⁷)
- highest in African/African American (1/75
- 066
- AF=1.33×10⁻⁵).
Sources
BP4 SupportingMultiple lines of computational evidence support a benign impact: REVEL score 0.046 (well below pathogenic thresholds), BayesDel score -0.448 (predicted benign), and SpliceAI max delta 0.00 (no splice alteration predicted). Details ▾Hide ▴
Evidence considered
- REVEL 0.046 (benign-leaning
- far below the typical ~0.5 pathogenic threshold)
- BayesDel -0.448 (negative score
- predicted benign)
- SpliceAI Δ=0.00 (no predicted splice impact).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No different nucleotide change at codon 1072 has been classified as pathogenic in ClinVar or published literature. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- No ClinVar entries exist for any variant at this codon
- no literature reports a different pathogenic nucleotide change at this position.
Sources
PS2 No de novo observation has been reported for this variant. No publications or ClinVar submissions describe a de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo data available from any source.
Still missing
- No trio or parent-of-origin testing data available.
PS3 No variant-specific functional data exists. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No publications describe experimental characterization of p.Ser1072Cys or a systematically characterized range that includes residue 1072. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified in literature or curated databases.
Still missing
- No in vitro or in vivo functional assay data for p.Ser1072Cys.
Sources
PS4 No variant prevalence data in affected individuals versus controls. The variant is absent from ClinVar and has not been reported in any published case series or cohorts. Details ▾Hide ▴
Evidence considered
- Variant not reported in ClinVar or literature
- no case-control comparison available.
Still missing
- No proband or cohort data available.
Sources
PM1 Residue 1072 is not in a statistically significant mutational hotspot (cancerhotspots.org: not significant). It lies in an inter-domain region between the KIX domain (~586-672) and the bromodomain (~1103-1175) and is not within a well-characterized functional domain with domain-level variant enrichment data. Details ▾Hide ▴
Evidence considered
- Not in a cancerhotspots.org significant hotspot
- residue 1072 is not within a characterized functional domain with established pathogenic enrichment.
PM5 No different pathogenic missense variant at codon 1072 has been identified. Automated PM5 candidate harvesting returned zero candidates at this residue. Details ▾Hide ▴
Evidence considered
- Zero same-codon comparator variants identified
- no pathogenic missense variants at residue 1072 in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation has been reported for this variant. No publications or ClinVar submissions describe a de novo occurrence of c.3215C>G. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or parental testing data available.
PP1 No segregation data is available for this variant. It has not been reported in any families or cosegregation studies. Details ▾Hide ▴
Evidence considered
- No family or cosegregation data available.
Still missing
- No multigenerational or affected-relative data.
PP2 While missense variants are a known disease mechanism in CREBBP, PP2 requires demonstrating a low rate of benign missense variation (e.g., via gnomAD missense Z-score or constraint metrics), which was not available in the case evidence. Details ▾Hide ▴
Evidence considered
- Missense variants are a known mechanism in CREBBP (24% of RSTS variants are missense)
- but gene-level missense constraint metrics were not available to satisfy PP2.
Still missing
- gnomAD missense Z-score or LOEUF metrics not retrieved for this gene.
PP3 Multiple in silico predictors support a benign impact: REVEL score 0.046 (below pathogenic threshold), BayesDel score -0.448 (predicted benign), SpliceAI max delta 0.00 (no splice impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.046 (benign-leaning)
- BayesDel -0.448 (predicted benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
PP4 No patient phenotype or family history data is available for this adjudication. PP4 requires a phenotype highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- No clinical phenotype information provided for the case.
PP5 The variant is absent from ClinVar. No reputable source or expert panel has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- No ClinVar entry exists for this variant
- no expert panel or reputable source classification available.
Sources
BA1 The highest population allele frequency is 0.00133% (African/African American, gnomAD v4.1), well below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 1.33×10⁻⁵ (AFR
- gnomAD v4.1)
- far below 1% BA1 threshold.
Sources
BS1 The highest population allele frequency is 0.00133% (African/African American, gnomAD v4.1), well below the BS1 threshold of 0.3% for a dominant disorder. Details ▾Hide ▴
Evidence considered
- Maximum population AF = 1.33×10⁻⁵ (AFR)
- far below 0.3% BS1 threshold.
Sources
BS2 A single allele was observed in gnomAD v4.1 (1/1,614,258), but this does not constitute confirmed observation in a healthy adult individual for a fully penetrant dominant disorder. The health status of the gnomAD individual is unknown. Details ▾Hide ▴
Evidence considered
- Single heterozygous observation in gnomAD v4.1
- insufficient to confirm healthy adult observation for BS2.
Still missing
- Health/phenotype status of the single gnomAD carrier is unknown.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. Details ▾Hide ▴
Evidence considered
- No functional studies exist for this variant showing a benign effect.
Still missing
- No functional assay data for p.Ser1072Cys.
Sources
BS4 No segregation data is available for this variant. Lack of segregation in affected family members cannot be assessed. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No family data to assess non-segregation.
BP1 Missense variants are a known disease mechanism in CREBBP. Among reported CREBBP RSTS variants, 24% are missense, indicating that missense variants are not an unexpected finding and BP1 does not apply. Details ▾Hide ▴
Evidence considered
- In a Polish RSTS cohort (PMID:41153422)
- 24% (4/17) of CREBBP variants were missense
- demonstrating that missense is an established mechanism in CREBBP.
BP2 No observation of this variant in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant (for a recessive disorder) is available. Details ▾Hide ▴
Evidence considered
- No phase or allelic data available.
Still missing
- No phasing data with other CREBBP variants.
BP5 No alternative molecular basis for disease has been identified in a case carrying this variant. No case-level diagnostic data is available. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis data available.
Still missing
- No proband genetic workup data available.
BP6 The variant is absent from ClinVar. No reputable source or expert panel has classified this variant as benign. Details ▾Hide ▴
PS5 No same amino acid change (p.Ser1072Cys) resulting from a different nucleotide substitution has been classified as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- No pathogenic variant producing p.Ser1072Cys via an alternative nucleotide change has been identified.
Sources
clinvar ↗pm5_candidates
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.3215C>G, p.Ser1072Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant — not in PVS1 null-variant buckets (nonsense
- frameshift
- canonical splice consensus).
Sources
BP7 N/AThis is a missense variant (c.3215C>G, p.Ser1072Cys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous — BP7 not applicable.
Identifiers
- Gene
- CREBBP
- Transcript
- NM_004380.2
- Coding (HGVS c.)
- NM_004380.2:c.3215C>G
- Protein (HGVS p.)
- NP_004371.2:p.(Ser1072Cys)
- GRCh38
- chr16:3767755 G>C
- GRCh37
- chr16:3817756 G>C
Gene diagram
Every interpreted variant in CREBBP, mapped onto the exon structure of NM_004380.2. Select a row to find it on the plot.
CREBBPNM_004380.2
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 CREBBP
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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
1 / 1,614,258 alleles
AF 6.19e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,258 alleles · 0 hom
| African/African American1 / 75,066 | 1.3e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.1948e-07; MAF= 0.00006%, 1/1614258 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33216e-05; MAF= 0.00133%, 1/75066 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.046
- BayesDel
- -0.448
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign impact: REVEL score 0.046 (well below pathogenic thresholds), BayesDel score -0.448 (predicted benign), and SpliceAI max delta 0.00 (no splice alteration predicted). Details ▾Hide ▴
Evidence considered
- REVEL 0.046 (benign-leaning
- far below the typical ~0.5 pathogenic threshold)
- BayesDel -0.448 (negative score
- predicted benign)
- SpliceAI Δ=0.00 (no predicted splice impact).
Sources
PP3 Multiple in silico predictors support a benign impact: REVEL score 0.046 (below pathogenic threshold), BayesDel score -0.448 (predicted benign), SpliceAI max delta 0.00 (no splice impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.046 (benign-leaning)
- BayesDel -0.448 (predicted benign)
- SpliceAI max delta 0.00 (no splice impact).
Sources
BP7 N/AThis is a missense variant (c.3215C>G, p.Ser1072Cys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous — BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.046. BayesDel score = -0.448244.
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
1 / 1,614,258 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
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_004380.2%3Ac.3215C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-3817756-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-3767755-G-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-3767755-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004380.2%3Ac.3215…
- OncoKB ↗www.oncokb.org/gene/CREBBP/S1072C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CREBBP+c.3215C%3EG
- 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= 6.1948e-07; MAF= 0.00006%, 1/1614258 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33216e-05; MAF= 0.00133%, 1/75066 alleles, homozygotes = 0).
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 = 0.046. BayesDel score = -0.448244.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CREBBP, a tumor suppressor and transcriptional co-activator, is frequently inactivated in hematologic malignancies.
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.