Variant classification summary

NM_004380.2:c.5671G>A

CREBBP · NP_004371.2:p.(Gly1891Arg) · NM_004380.2

GRCh37: chr16:3779377 C>T · GRCh38: chr16:3729376 C>T

Gene: CREBBP Transcript: NM_004380.2

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.(Gly1891Arg)

gnomAD AF

3.1077558397839986e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

6

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).

7

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	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.	clinvar
PS2	Not assessed	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.	clinvar
PS3	Not assessed	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.	oncokb
PS4	Not met	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.	gnomad_v4
PS5	Not assessed	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.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 clinvar
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	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).	clinvar
PP1	Not assessed	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.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Not assessed	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.	clinvar
BA1	Not met	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.	gnomad_v4
BS1	Not met	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.	gnomad_v4
BS2	Not assessed	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.	gnomad_v4
BS3	Not assessed	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.	oncokb
BS4	Not assessed	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.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not assessed	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.	clinvar
BP7	Not met	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.

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