About CREBBP
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CREBBP c.3780-2A>G, p.?
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
This variant alters the canonical splice acceptor at position -2 of intron 20 in CREBBP (NM_004380.2:c.3780-2A>G). CREBBP loss of function is an established mechanism for Rubinstein-Taybi syndrome, an autosomal-dominant neurodevelopmental disorder. Under the ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with established LoF disease mechanisms are eligible for PVS1 at full strength. The variant is absent from population databases (gnomAD v4.1: 0/1,591,234 alleles), consistent with a pathogenic splice-altering variant under purifying selection. No downgrade factors are present: the affected exon is not absent from biologically relevant transcripts, and population LoF constraint data does not suggest tolerance.
PM2Moderate
PM2 · moderate
This variant is absent from large population databases. In gnomAD v4.1, it is observed at 0/1,591,234 alleles (AF=0.000%), including 0/74656 African/African American alleles. It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, absence from population databases at an allele frequency well below 0.1% meets PM2 at moderate strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
0 / 1,591,234 alleles
gnomAD v4.1: 0 / 1,591,234 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
1.000 maximum delta
Recorded SpliceAI maximum delta score: 1.000. 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 ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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 · 18 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_004380.2:c.3780-2A>G is a canonical splice acceptor variant (position -2 of intron 20) in CREBBP, a gene in which loss of function is an established mechanism for autosomal-dominant Rubinstein-Taybi syndrome.
Under the ClinGen SVI PVS1 decision tree (PMC6185798), this canonical ±1,2 splice variant meets PVS1 at very strong strength given the established CREBBP loss-of-function disease mechanism and absence of downgrade factors.
The variant is absent from gnomAD v4.1 (0/1,591,234 alleles) and gnomAD v2.1, meeting PM2 at moderate strength.
SpliceAI strongly predicts an effect on splicing (max delta 1.0, acceptor gain 1.0, acceptor loss 0.99), and BayesDel predicts a deleterious score of 0.66, consistent with a pathogenic splice-altering variant. These in silico predictions are not separately credited under PP3 per PVS1 stacking guidance.
The variant is absent from ClinVar, and no published case reports, functional studies, or de novo reports were identified for NM_004380.2:c.3780-2A>G in the available literature.
Overall, the variant meets 1 very strong criterion (PVS1) and 1 moderate criterion (PM2). No benign criteria are met. Per the ACMG/AMP 2015 scoring rubric (1 very strong + 1 moderate), this variant is classified as PATHOGENIC.
No criteria match.
Met · 2
PVS1 Very strongThis variant alters the canonical splice acceptor at position -2 of intron 20 in CREBBP (NM_004380.2:c.3780-2A>G). CREBBP loss of function is an established mechanism for Rubinstein-Taybi syndrome, an autosomal-dominant neurodevelopmental disorder. Under the ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with established LoF disease mechanisms are eligible for PVS1 at full strength. The variant is absent from population databases (gnomAD v4.1: 0/1,591,234 alleles), consistent with a pathogenic splice-altering variant under purifying selection. No downgrade factors are present: the affected exon is not absent from biologically relevant transcripts, and population LoF constraint data does not suggest tolerance. Details ▾Hide ▴
Evidence considered
- Canonical splice acceptor variant (c.3780-2A>G) at the -2 position of intron 20
- CREBBP loss of function is an established disease mechanism for Rubinstein-Taybi syndrome (autosomal dominant)
- Gene eligible for generic PVS1 under PMC6185798
- variant bucket: canonical_splice
- Absent from gnomAD v4.1 (0/1
- 591
- 234 alleles) and gnomAD v2.1
- SpliceAI predicts strong splice disruption (max delta 1.0
- DS_AG=1.0
- DS_AL=0.99)
Sources
PM2 ModerateThis variant is absent from large population databases. In gnomAD v4.1, it is observed at 0/1,591,234 alleles (AF=0.000%), including 0/74656 African/African American alleles. It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, absence from population databases at an allele frequency well below 0.1% meets PM2 at moderate strength. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 591
- 234 alleles (AF=0.000%)
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
- Highest subpopulation frequency: African/African American 0/74
- 656 alleles
Sources
Not met · 18 · evaluated, threshold not reached
PS2 No de novo data are available for this variant. No published case reports or clinical submissions document a de novo occurrence confirmed by parental testing. Details ▾Hide ▴
Still missing
- Parental testing results not available
PS3 No functional data exist for NM_004380.2:c.3780-2A>G or a systematically characterized range that includes this variant. No experimental studies (saturation mutagenesis, tiling screen, or systematic truncation series) have characterized the intron 20 splice acceptor region. Domain-level inference from gene-level functional studies does not satisfy PS3 requirements. Details ▾Hide ▴
Still missing
- No functional characterization of this splice variant or a systematically assayed range that includes position c.3780-2
PS4 This variant is absent from ClinVar and has not been reported in any published case series or cohort studies. No case-control data or odds-ratio statistics are available to support statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- No published case reports or cohort studies identified
Still missing
- No case-control or prevalence data available
Sources
PM1 While CREBBP contains well-characterized functional domains (KIX, bromodomain, HAT/KAT11), the specific region affected by loss of the intron 20 splice acceptor has not been identified as a mutational hotspot or critical functional domain with limited benign variation. No cancerhotspots.org significance was found for this residue. Without domain-specific evidence demonstrating that this region is intolerant to variation, PM1 cannot be applied. Details ▾Hide ▴
Evidence considered
- CREBBP has known functional domains but no mutational hotspot at this region
- No domain-level constraint data specific to the intron 20 acceptor region
Still missing
- Domain-level characterization of the region affected by the intron 20 splice disruption is not available in the case materials
PM6 No de novo occurrence has been documented for this variant. The published literature on CREBBP-related Rubinstein-Taybi syndrome describes splice-site variants generally but does not report NM_004380.2:c.3780-2A>G specifically as a de novo event. Details ▾Hide ▴
Still missing
- Parental testing required for de novo confirmation
PP1 No co-segregation data are available for this variant. No family studies have been published demonstrating co-segregation with Rubinstein-Taybi syndrome or any other CREBBP-related phenotype. Details ▾Hide ▴
Still missing
- No family studies or co-segregation analysis available
PP3 Multiple in silico tools predict a deleterious effect (SpliceAI max delta 1.0, DS_AG=1.0, DS_AL=0.99; BayesDel 0.66). However, under PMC6185798 guidance, computational splice prediction evidence should not be double-counted when PVS1 has already been applied for a canonical splice variant. The in silico evidence supporting splice disruption is already captured in the PVS1 assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 1.0 (DS_AG=1.0
- DS_AL=0.99
- Pangolin SG=0.89)
- BayesDel: 0.66 (deleterious)
Sources
spliceai ↗bayesdel
PP4 No phenotype specificity data are available for this variant. While CREBBP variants are associated with Rubinstein-Taybi syndrome, no clinical data confirm that this specific proband's phenotype is highly specific for CREBBP-related disease. Details ▾Hide ▴
Still missing
- Proband phenotype details not available in case materials
PP5 This variant is absent from ClinVar. No expert panel or reputable clinical laboratory has submitted a classification for NM_004380.2:c.3780-2A>G, so there is no external classification to credit under PP5. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v4.1 (0/1,591,234 alleles, AF=0.000%), far below the BA1 threshold of >1%. It does not meet the population frequency requirement for a stand-alone benign classification. Details ▾Hide ▴
BS1 This variant is absent from gnomAD (AF=0.000%), far below the BS1 threshold of >0.3%. The population frequency data do not support a benign interpretation. Details ▾Hide ▴
BS2 BS2 requires observation of the variant in a healthy adult individual with full penetrance expected at an early age. No such observation exists for NM_004380.2:c.3780-2A>G. The variant is entirely absent from population databases and no healthy control carriers have been reported. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no healthy carriers identified
Sources
BS3 No functional studies have assessed NM_004380.2:c.3780-2A>G. No experimental data demonstrate that this splice variant has no deleterious effect on protein function or splicing. Details ▾Hide ▴
Still missing
- No functional data available to support a benign effect
BS4 No lack of segregation data are available. No family studies have been performed to assess whether the variant fails to segregate with disease in affected families. Details ▾Hide ▴
Still missing
- No family studies available to evaluate segregation
BP2 No observation of this variant in trans with a known pathogenic CREBBP variant has been reported. In the absence of such data, BP2 cannot be applied. Details ▾Hide ▴
Still missing
- No data on trans configuration with other pathogenic variants
BP4 Multiple lines of computational evidence predict a deleterious effect. SpliceAI indicates strong splice disruption (max delta 1.0; DS_AG=1.0, DS_AL=0.99) and BayesDel predicts a deleterious score of 0.66. These predictions are inconsistent with a benign interpretation and do not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 1.0 (strong splice-altering prediction)
- BayesDel: 0.66 (deleterious prediction)
Sources
spliceai ↗bayesdel
BP5 No data are available demonstrating that this variant has been observed in a case with a definitive alternate molecular basis for disease. BP5 requires a specific alternative explanation for the observed phenotype, which has not been established. Details ▾Hide ▴
Still missing
- No information on alternate molecular diagnoses in the proband
BP6 This variant is absent from ClinVar. No reputable source has classified NM_004380.2:c.3780-2A>G as benign or likely benign, so there is no external benign classification to credit under BP6. Details ▾Hide ▴
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis is a canonical splice site variant, not a missense change. PS1 requires the same amino acid change as a previously established pathogenic variant, which is not applicable to splice-altering variants. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. This is a canonical splice site variant (c.3780-2A>G) with no defined protein consequence, making PM5 structurally inapplicable. The pm5_candidates pipeline confirmed no eligible same-residue comparators. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a canonical splice site variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is primarily causative. This is a canonical splice site variant predicted to cause aberrant splicing and likely loss of function, not a missense change with an alternative molecular basis. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This is a canonical splice site variant (c.3780-2A>G), not a synonymous variant, and splice prediction algorithms predict a strong deleterious effect. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 requires a distinct pathogenic variant at the same amino acid position. This is a canonical splice site variant with no defined amino acid position, making PS5 inapplicable. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CREBBP
- Transcript
- NM_004380.2
- Coding (HGVS c.)
- NM_004380.2:c.3780-2A>G
- Protein (HGVS p.)
- NP_004371.2:p.?
- GRCh38
- chr16:3749685 T>C
- GRCh37
- chr16:3799686 T>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
0 / 1,591,234 alleles
AF 0 · 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 0 · 0 / 1,591,234 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1591234 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74656 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
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 Multiple in silico tools predict a deleterious effect (SpliceAI max delta 1.0, DS_AG=1.0, DS_AL=0.99; BayesDel 0.66). However, under PMC6185798 guidance, computational splice prediction evidence should not be double-counted when PVS1 has already been applied for a canonical splice variant. The in silico evidence supporting splice disruption is already captured in the PVS1 assessment. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 1.0 (DS_AG=1.0
- DS_AL=0.99
- Pangolin SG=0.89)
- BayesDel: 0.66 (deleterious)
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence predict a deleterious effect. SpliceAI indicates strong splice disruption (max delta 1.0; DS_AG=1.0, DS_AL=0.99) and BayesDel predicts a deleterious score of 0.66. These predictions are inconsistent with a benign interpretation and do not support BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 1.0 (strong splice-altering prediction)
- BayesDel: 0.66 (deleterious prediction)
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This is a canonical splice site variant (c.3780-2A>G), not a synonymous variant, and splice prediction algorithms predict a strong deleterious effect. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.
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
0 / 1,591,234 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 1.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004380.2%3Ac.3780-2A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/16-3799686-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr16-3749685-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/16-3749685-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004380.2%3Ac.3780…
- OncoKB ↗www.oncokb.org/gene/CREBBP/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CREBBP+c.3780-2A%3EG
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= 0; MAF= 0.00000%, 0/1591234 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74656 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 possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).