About CREBBP
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CREBBP c.5671G>A, p.(Gly1891Arg)
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
The variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF = 3.11e-6; 5/1,608,878 alleles; no homozygotes). This is well below the 0.1% PM2 threshold for dominant disorders under generic ACMG/AMP rules. The variant is also absent from ClinVar and gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene or gene product. SpliceAI predicts no splice alteration (max delta = 0.00). REVEL score is 0.388, below the typical pathogenic cutoff. BayesDel score is -0.135549, in the benign/neutral range. No in silico predictor supports a deleterious effect.
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
5 / 1,608,878 alleles
gnomAD v4.1: 5 / 1,608,878 alleles. Recorded AF 3.10776e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
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 · 8 not met · 14 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
CREBBP NM_004380.2:c.5671G>A (p.Gly1891Arg) is a missense variant in exon 31 of CREBBP, a gene associated with autosomal dominant Rubinstein-Taybi syndrome through haploinsufficiency and loss-of-function mechanisms.
The variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (allele frequency 3.11e-6; 5/1,608,878 alleles; no homozygotes), meeting PM2 at supporting strength for a dominant disorder.
Multiple in silico tools do not support a deleterious effect: SpliceAI predicts no splice alteration (max delta = 0.00), REVEL score is 0.388 (below typical pathogenic threshold), and BayesDel score is -0.135549 (benign range), meeting BP4 at supporting benign strength.
The variant is absent from ClinVar, and no published literature specifically reporting NM_004380.2:c.5671G>A was identified across five screened abstracts addressing CREBBP in germline disease contexts.
No functional studies, de novo observations, co-segregation data, or case-control evidence was identified for this variant. PVS1 is not applicable as the variant is missense, not a null variant.
Under generic ACMG/AMP 2015 combination rules, the applicable criteria are PM2 (supporting) and BP4 (supporting benign). These partially offset, resulting in an overall classification of Variant of Uncertain Significance (VUS).
The observation of five carriers in gnomAD v4.1 (including one in the African/African American subpopulation) without homozygotes is noted; however, in the absence of individual-level phenotype data, this does not independently establish benignity. The gnomAD filtering allele frequency (grpmax FAF = 7.9e-7) confirms extreme rarity.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 and present at an extremely low allele frequency in gnomAD v4.1 (AF = 3.11e-6; 5/1,608,878 alleles; no homozygotes). This is well below the 0.1% PM2 threshold for dominant disorders under generic ACMG/AMP rules. The variant is also absent from ClinVar and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: AF = 3.11e-6 (5/1
- 608
- 878)
- highest subpopulation AF = 1.34e-5 (African/African American)
- grpmax FAF = 7.9e-7
- zero homozygotes. ClinVar: absent.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene or gene product. SpliceAI predicts no splice alteration (max delta = 0.00). REVEL score is 0.388, below the typical pathogenic cutoff. BayesDel score is -0.135549, in the benign/neutral range. No in silico predictor supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (all delta scores = 0.00). REVEL: 0.388 (below pathogenic threshold of ~0.5-0.75). BayesDel: -0.135549 (negative
- consistent with benign).
Sources
Not met · 8 · evaluated, threshold not reached
PS4 PS4 requires statistically significant enrichment of the variant in affected individuals versus controls. The variant is extremely rare in gnomAD v4.1 (AF = 3.11e-6), but no case counts from affected individuals are available. Without independent observations in RSTS probands, prevalence in cases cannot be compared to population controls. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 5/1
- 608
- 878 alleles (AF = 3.11e-6). No proband counts available from ClinVar or literature.
Still missing
- Need independent proband observations from clinical laboratories or published case series.
Sources
PM1 PM1 requires location in a mutational hot spot or well-established critical functional domain without benign variation. Gly1891 resides in the C-terminal region of CREBBP, near the nuclear receptor coactivator binding domain (NCBD). Cancer Hotspots does not identify this residue as statistically significant. There is no established germline mutational hotspot at this position in RSTS. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not significant. Exploratory agent confirms Gly1891 is not in a well-defined mutational hotspot like the HAT domain.
Still missing
- Domain-level constraint data (e.g.
- regional missense constraint) could refine this assessment.
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.388 (below the typical 0.5-0.75 pathogenic threshold). BayesDel score is -0.135549 (negative, suggesting benign/neutral). SpliceAI max delta is 0.00 (no predicted splice impact). The in silico evidence does not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.388. BayesDel: -0.135549. SpliceAI: max delta = 0.00 (all four delta scores = 0.00). HCI prior: not available (gene not supported).
Sources
BA1 BA1 requires an allele frequency >1% in any general population database. The variant's maximum allele frequency in gnomAD v4.1 is 1.34e-5 (African/African American subpopulation), far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 3.11e-6 overall
- max subpopulation AF = 1.34e-5 (African/African American).
Sources
BS1 BS1 requires an allele frequency >0.3% for a dominant disorder. The variant's maximum allele frequency is 1.34e-5, far below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF = 3.11e-6
- max subpopulation AF = 1.34e-5 (0.0013%). Both well below 0.3% BS1 threshold.
Sources
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. In CREBBP-associated RSTS, missense variants are an established disease mechanism. PMID:41153422 reports 4/17 (24%) of RSTS-causing variants in their cohort were missense. Therefore, CREBBP does not meet the 'primarily truncating' criterion for BP1. Details ▾Hide ▴
Evidence considered
- PMID:41153422: In 17 RSTS patients
- variant types included missense (4/17
- 24%)
- frameshift (6/17
- 35%)
- nonsense (3/17
- 18%)
- splice-site (2/17
- 12%)
- and gross deletions (2/17
- 12%). Missense is a recognized pathogenic mechanism in CREBBP.
Sources
pvs1_gene_context41153422
BP2 BP2 requires observation in trans with a known pathogenic variant for a fully penetrant dominant disorder. No such observation has been reported. Biallelic CREBBP variants would be expected to be embryonic lethal or extremely severe. Details ▾Hide ▴
Evidence considered
- No evidence of co-occurrence with another CREBBP pathogenic variant in trans.
BP7 BP7 applies to synonymous variants predicted to have no splice impact. NM_004380.2:c.5671G>A is a missense variant producing p.Gly1891Arg, not a synonymous variant. BP7 is not applicable to missense changes. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.5671G>A
- p.Gly1891Arg)
- not synonymous. BP7 restricted to silent/synonymous variants.
Not assessed · 14 · no assessment recorded
PS1 PS1 requires a different nucleotide change at the same codon producing the same amino acid change previously established as pathogenic. No ClinVar or literature evidence identifies a pathogenic variant at CREBBP Gly1891 arising from a different nucleotide substitution. This variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar. No alternate nucleotide changes producing p.Gly1891Arg with established pathogenicity were identified.
Still missing
- No ClinVar records exist for this variant or any same-residue comparator.
Sources
PS2 PS2 requires a confirmed de novo observation (maternity and paternity confirmed) in a patient with CREBBP-associated disease. Although the exploratory agent noted a possible de novo submission in ClinVar, structured ClinVar data confirms the variant is absent from ClinVar (no variation IDs, zero submissions, empty submission audit). No published de novo observations for NM_004380.2:c.5671G>A were identified in the screened literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entry for this variant. Clinvar_submission_audit is empty. Literature_pass returned zero PMIDs. Five reviewed abstracts (PMID:41153422
- 31806049
- 35275800
- 35638907
- 37427096) do not mention this variant.
Still missing
- Direct ClinVar search or targeted PubMed search for de novo reports of c.5671G>A may yield additional information not captured in automated harvesting.
Sources
PS3 PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect. No functional characterization of p.Gly1891Arg was identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies found. Exploratory agent found no functional assay data for p.Gly1891Arg.
Still missing
- No functional studies (HAT activity
- transcriptional activation
- protein interaction) have been identified for CREBBP p.Gly1891Arg.
Sources
PM6 PM6 requires a de novo observation without confirmation of both parents. As with PS2, the structured ClinVar data shows the variant is absent from ClinVar, and no published de novo reports for this specific variant were identified. If a de novo observation is later confirmed without parental testing documentation, PM6 could be considered (and would supersede PS2). Details ▾Hide ▴
Evidence considered
- ClinVar: no entries. Literature_pass: zero PMIDs. No de novo evidence identified.
Still missing
- Same gap as PS2: clinical laboratory submissions or case reports may document de novo occurrence.
Sources
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. No segregation data was identified. Most RSTS cases are sporadic due to de novo occurrence, making familial co-segregation data inherently scarce. Details ▾Hide ▴
Evidence considered
- No segregation data identified. RSTS is predominantly sporadic (de novo)
- limiting availability of familial co-segregation evidence.
PP2 PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. While missense variants are a known mechanism in CREBBP-associated RSTS, gnomAD missense constraint metrics (Z-score, observed/expected ratio) were not available in the evidence packet to assess whether CREBBP has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- CREBBP is a known RSTS gene with both truncating and missense pathogenic variants. GnomAD constraint data not available for PP2 assessment.
Still missing
- gnomAD gene constraint metrics (missense Z-score
- o/e ratio) needed to determine if CREBBP qualifies for PP2.
PP4 PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. No patient-specific phenotypic data was available in the evidence packet. In addition, PP4 applies at the case level and requires clinical context. Details ▾Hide ▴
Evidence considered
- No patient phenotype or family history data available.
Still missing
- Patient clinical phenotype and family history are needed to assess PP4.
PP5 PP5 requires a reputable source to have reported this variant as pathogenic with supporting evidence. The variant is absent from ClinVar and was not identified in the screened literature. No such report exists. Details ▾Hide ▴
BS2 BS2 requires observation in a healthy adult individual for a fully penetrant dominant disorder. No data on individual phenotypes of the five gnomAD v4.1 carriers is available. The gnomAD population is generally considered healthy but contains individuals with late-onset conditions, so observation alone is insufficient for BS2 without phenotypic confirmation. Details ▾Hide ▴
Evidence considered
- Five carriers in gnomAD v4.1 (zero homozygotes)
- but no individual-level phenotype data available. RSTS is a congenital disorder with distinctive features that would likely preclude inclusion in population databases if fully penetrant.
Still missing
- Individual-level phenotypes of gnomAD carriers are not accessible.
Sources
BS3 BS3 requires well-established functional studies showing no damaging effect. No functional characterization of p.Gly1891Arg was identified. Neither damaging nor benign functional evidence exists for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies of p.Gly1891Arg identified.
Still missing
- No functional assay data (HAT activity
- transactivation
- protein binding) available for this variant.
Sources
BS4 BS4 requires non-segregation with disease in affected members of a family. No segregation data was identified. RSTS is predominantly sporadic, and no family studies including this variant were found. Details ▾Hide ▴
Evidence considered
- No segregation data available.
BP5 BP5 requires observation of the variant in a case with an alternative molecular basis for disease. No case-level data including co-occurring genetic findings is available. Details ▾Hide ▴
Evidence considered
- No case-level molecular data available.
Still missing
- Patient-level genetic testing results needed.
BP6 BP6 requires a reputable source to report the variant as benign without the evaluator independently reviewing the evidence. The variant is absent from ClinVar and was not identified in the screened literature as benign. No such report exists. Details ▾Hide ▴
PS5 PS5 requires a reputable source to have reported this exact variant as pathogenic with supporting evidence that is not independently verified by the evaluator. The variant is absent from ClinVar and was not identified in the screened literature. No such report exists to rely on. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar. No PMIDs identified through literature_pass.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004380.2:c.5671G>A is a missense variant (p.Gly1891Arg). PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, single/multi-exon deletions). This variant does not fall into any PVS1 null-variant bucket under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant type is missense (substitution). pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/APM5 requires a different missense change at the same residue previously established as pathogenic. No same-residue pathogenic comparator variants were identified through automated ClinVar candidate harvesting. The PM5 candidate collection returned zero candidates. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: found=false
- zero same-residue candidates
- recommendation level=not_applicable.
Sources
pm5_candidates
Identifiers
- Gene
- CREBBP
- Transcript
- NM_004380.2
- Coding (HGVS c.)
- NM_004380.2:c.5671G>A
- Protein (HGVS p.)
- NP_004371.2:p.(Gly1891Arg)
- GRCh38
- chr16:3729376 C>T
- GRCh37
- chr16:3779377 C>T
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
5 / 1,608,878 alleles
AF 3.11e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,608,878 alleles · 0 hom · FAF 7.9e-07
| African/African American1 / 74,808 | 1.3e-05 |
| European (non-Finnish)4 / 1,179,576 | 3.4e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.10776e-06; MAF= 0.00031%, 5/1608878 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33676e-05; MAF= 0.00134%, 1/74808 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.388
- BayesDel
- -0.136
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene or gene product. SpliceAI predicts no splice alteration (max delta = 0.00). REVEL score is 0.388, below the typical pathogenic cutoff. BayesDel score is -0.135549, in the benign/neutral range. No in silico predictor supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (all delta scores = 0.00). REVEL: 0.388 (below pathogenic threshold of ~0.5-0.75). BayesDel: -0.135549 (negative
- consistent with benign).
Sources
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. REVEL score is 0.388 (below the typical 0.5-0.75 pathogenic threshold). BayesDel score is -0.135549 (negative, suggesting benign/neutral). SpliceAI max delta is 0.00 (no predicted splice impact). The in silico evidence does not support a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.388. BayesDel: -0.135549. SpliceAI: max delta = 0.00 (all four delta scores = 0.00). HCI prior: not available (gene not supported).
Sources
BP7 BP7 applies to synonymous variants predicted to have no splice impact. NM_004380.2:c.5671G>A is a missense variant producing p.Gly1891Arg, not a synonymous variant. BP7 is not applicable to missense changes. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.5671G>A
- p.Gly1891Arg)
- not synonymous. BP7 restricted to silent/synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.388. BayesDel score = -0.135549.
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
5 / 1,608,878 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.5671G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-3779377-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-3729376-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004380.2%3Ac.5671…
- OncoKB ↗www.oncokb.org/gene/CREBBP/G1891R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CREBBP+c.5671G%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= 3.10776e-06; MAF= 0.00031%, 5/1608878 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33676e-05; MAF= 0.00134%, 1/74808 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
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). REVEL score = 0.388. BayesDel score = -0.135549.
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.