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CREBBPc.3710G>CUncertain significance
Print report
Variant interpretation report

CREBBP c.3710G>C, p.(Cys1237Ser)

NM_004380.2:c.3710G>C NP_004371.2:p.(Cys1237Ser) View identifiers
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.

About CREBBP

No gene-level summary was recorded for this case.

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
PM2Moderate
PM2 · moderate

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Allele frequency of 0% is well below the PM2 threshold of <0.1%.

PP3Supporting
PP3 · supporting

Multiple in silico predictors support a deleterious effect. REVEL score is 0.922, which is well above the pathogenic threshold of 0.5. BayesDel additive score is 0.549, also above the deleterious threshold of 0.27. SpliceAI predicts no significant splice impact (max delta 0.13), which is expected for a missense variant.

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, PP3 supporting; combination = 1 moderate + 1 supporting, 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.

SpliceAI score
0.130 maximum delta

Recorded SpliceAI maximum delta score: 0.130. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → 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. CREBBP, a tumor suppressor and transcriptional co-activator, is frequently inactivated in hematologic malignancies.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV108055186, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 11 not met · 8 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This variant is absent from population databases (gnomAD v2.1, v4.1, Canada; AF=0%), meeting PM2 at moderate strength.

Multiple in silico predictors support a deleterious effect: REVEL score 0.922 is strongly pathogenic, and BayesDel additive score 0.549 supports deleteriousness, meeting PP3 at supporting strength.

No other pathogenic criteria were met. PVS1 is not applicable (missense variant). PS3 was not met (no functional data identified). PS1, PS4, PS5, PM1, PM5, and PP5 did not yield evidence for this variant.

No benign criteria were met. BA1 and BS1 are not met (variant absent from population databases). BP1 is not met (missense variants are established in CREBBP disease). BP4 is not met (in silico predictors favor pathogenicity).

Total evidence: 1 moderate pathogenic criterion (PM2) + 1 supporting pathogenic criterion (PP3). This does not meet the threshold for Likely Pathogenic (requires 2 moderate + 2 supporting, or 1 moderate + 4 supporting, or 1 strong + 2 supporting, etc.) per generic ACMG/AMP 2015 combination rules.

The variant is classified as a Variant of Uncertain Significance (VUS). The missense substitution p.Cys1237Ser in the PHD finger domain of CREBBP, complete absence from population databases, and concordant in silico predictions warrant further investigation including functional studies, segregation analysis, and clinical correlation.

Met · 2

PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases. Allele frequency of 0% is well below the PM2 threshold of <0.1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF=0)
  • gnomAD v4.1 (AF=0)
  • and gnomAD-Canada v1.0 (AF=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score is 0.922, which is well above the pathogenic threshold of 0.5. BayesDel additive score is 0.549, also above the deleterious threshold of 0.27. SpliceAI predicts no significant splice impact (max delta 0.13), which is expected for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.922 (pathogenic). BayesDel additive score: 0.549 (deleterious). SpliceAI max delta: 0.13 (no splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 11 · evaluated, threshold not reached

PS1 No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution (p.Cys1237Ser) that is established as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no pathogenic variants at this codon with a different nucleotide change were identified.
Sources
clinvar ↗
PS3 No functional studies were identified for this variant. OncoKB reports an unknown oncogenic effect, and no literature PMIDs with variant-specific functional data were found. REVEL and BayesDel are in silico predictors, not functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect. No variant-specific functional data identified in the literature.
Still missing
  • No functional studies available for this variant.
Sources
oncokb ↗
PS4 No prevalence data available. The variant is absent from ClinVar, providing no evidence of enrichment in affected individuals versus controls. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no affected individuals identified.
Still missing
  • No case-control or prevalence data available.
Sources
clinvar ↗
PM1 Position 1237 lies within the PHD finger zinc-binding domain of CREBBP, which is a recognized functional domain. However, cancerhotspots.org does not identify this residue as a statistically significant hotspot. Domain-level PM1 application requires evidence that missense variants in this domain are established as pathogenic, which was not identified in the case materials. No domain-specific functional characterization of position 1237 was available. Details ▾Hide ▴
Evidence considered
  • Residue 1237 is within the PHD finger domain of CREBBP but is not a statistically significant hotspot (cancerhotspots.org). No domain-level missense constraint or mutational enrichment data available.
Still missing
  • No domain-specific evidence characterizing the PHD finger as a missense-enriched pathogenic domain for CREBBP.
PM5 No pathogenic missense variants at the same amino acid residue (Cys1237) were identified in ClinVar. The automated PM5 candidate search found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • Zero pathogenic missense variants at the same amino acid residue identified in ClinVar.
Sources
pm5_candidatesclinvar ↗
PP2 The HCI prior missense constraint score is not available for CREBBP. Without a missense Z-score or regional constraint metric demonstrating that missense variation is a recognized disease mechanism with low benign missense variation, PP2 cannot be applied. Although CREBBP missense variants are known to cause Rubinstein-Taybi syndrome, PP2 requires quantitative missense constraint data. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for CREBBP. No missense Z-score or constraint metric data available.
Still missing
  • Missense constraint data (e.g.
  • gnomAD missense Z-score
  • MTR
  • or regional constraint) not available for CREBBP.
BA1 The variant is absent from gnomAD (AF=0%), far below the BA1 threshold of >1% allele frequency in population databases. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The variant is absent from gnomAD (AF=0%), far below the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 and v4.1.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating no damaging effect were identified. OncoKB reports an unknown oncogenic effect, which does not constitute evidence of normal function. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect. No benign functional data identified.
Still missing
  • No functional studies demonstrating normal protein function.
Sources
oncokb ↗
BP1 CREBBP missense variants are established causes of Rubinstein-Taybi syndrome. PMID:41153422 reports that 24% of pathogenic CREBBP variants in a Polish RSTS cohort were missense. BP1 applies only when a gene is associated with disease exclusively through truncating variants, which is not the case for CREBBP. Details ▾Hide ▴
Evidence considered
  • CREBBP missense variants are established causes of Rubinstein-Taybi syndrome (PMID:41153422).
BP4 Multiple in silico predictors support a deleterious effect, not a benign impact. REVEL score is 0.922 (pathogenic) and BayesDel additive score is 0.549 (deleterious). SpliceAI shows no significant splice impact (max delta 0.13), but this does not constitute evidence of a benign effect for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.922 (pathogenic). BayesDel: 0.549 (deleterious). SpliceAI max delta: 0.13 (no splicing impact — neutral for missense).
Sources
revelbayesdelspliceai ↗

Not assessed · 8 · no assessment recorded

PS2 No de novo data available in the case materials. No family studies or parental testing results were provided. Details ▾Hide ▴
Still missing
  • Parental testing data not available
  • de novo status cannot be determined.
PM6 No de novo data available. No confirmed de novo reports for this variant were identified in the case materials or literature. Details ▾Hide ▴
Still missing
  • Parental testing not performed
  • de novo status unknown.
PP1 No segregation data available. No family studies were provided in the case materials. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP4 No patient phenotype data was provided. The patient's clinical features are not available for comparison with CREBBP-associated Rubinstein-Taybi syndrome. Details ▾Hide ▴
Still missing
  • Patient phenotype not provided.
BS2 No data on observation in healthy adults with complete penetrance expected at an early age. The variant is absent from population databases, so BS2 cannot be applied. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available.
BS4 No segregation data available. Lack of cosegregation with disease in affected families cannot be evaluated. Details ▾Hide ▴
Still missing
  • No family segregation data.
BP2 No data on observation in trans with a known pathogenic variant. CREBBP-associated Rubinstein-Taybi syndrome is autosomal dominant, so in trans observations are unlikely. Details ▾Hide ▴

No further detail was recorded.

BP5 No alternative molecular diagnosis data available. A different disease-causing variant explaining the phenotype was not reported. Details ▾Hide ▴
Still missing
  • No alternative molecular diagnosis reported.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.3710G>C, p.Cys1237Ser); it does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a substitution (missense)
  • not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo evidence for a recessive disorder; CREBBP-associated disease is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a substitution variant, not an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

PP5 N/AThe variant is absent from ClinVar. No reputable source has classified this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant not present in ClinVar.
Sources
clinvar ↗
BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion in a non-repeat region. Details ▾Hide ▴

No further detail was recorded.

BP6 N/AThe variant is absent from ClinVar. No reputable source has classified this variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant not present in ClinVar.
Sources
clinvar ↗
BP7 N/AThis is a missense variant (c.3710G>C, p.Cys1237Ser), not a synonymous variant. BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact. SpliceAI max delta score is 0.13, consistent with no splice effect, but the criterion is structurally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous. SpliceAI max delta: 0.13.
Sources
spliceai ↗
PS5 N/AThe variant is absent from ClinVar. No reputable source has reported this variant as pathogenic with evidence unavailable for independent evaluation. Details ▾Hide ▴
Evidence considered
  • Variant not present in ClinVar.
Sources
clinvar ↗

Identifiers

Gene
CREBBP
Transcript
NM_004380.2
Coding (HGVS c.)
NM_004380.2:c.3710G>C
Protein (HGVS p.)
NP_004371.2:p.(Cys1237Ser)
GRCh38
chr16:3751795 C>G
GRCh37
chr16:3801796 C>G
COSMIC
COSV108055186

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…
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

SpliceAI acceptor lossat +11 bp
0.020
SpliceAI acceptor gainat -8 bp
0.130
SpliceAI donor lossat -69 bp
0.000
SpliceAI donor gainat +12 bp
0.000

Other predictors

REVEL
0.922
BayesDel
0.549

How the predictions were used

PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score is 0.922, which is well above the pathogenic threshold of 0.5. BayesDel additive score is 0.549, also above the deleterious threshold of 0.27. SpliceAI predicts no significant splice impact (max delta 0.13), which is expected for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.922 (pathogenic). BayesDel additive score: 0.549 (deleterious). SpliceAI max delta: 0.13 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP4 Multiple in silico predictors support a deleterious effect, not a benign impact. REVEL score is 0.922 (pathogenic) and BayesDel additive score is 0.549 (deleterious). SpliceAI shows no significant splice impact (max delta 0.13), but this does not constitute evidence of a benign effect for a missense variant. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.922 (pathogenic). BayesDel: 0.549 (deleterious). SpliceAI max delta: 0.13 (no splicing impact — neutral for missense).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.3710G>C, p.Cys1237Ser), not a synonymous variant. BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact. SpliceAI max delta score is 0.13, consistent with no splice effect, but the criterion is structurally inapplicable to missense variants. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous. SpliceAI max delta: 0.13.
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.922. BayesDel score = 0.549047.

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 0.130 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

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 = 0.13). REVEL score = 0.922. BayesDel score = 0.549047.

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 previously been reported in somatic cancers (COSMIC; COSV108055186, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.