Variant classification summary

NM_004380.2:c.3710G>C

CREBBP · NP_004371.2:p.(Cys1237Ser) · NM_004380.2

GRCh37: chr16:3801796 C>G · GRCh38: chr16:3751795 C>G

Gene: CREBBP Transcript: NM_004380.2

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.(Cys1237Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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.

3

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.

4

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).

5

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.

6

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.

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	This 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).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not assessed	No de novo data available in the case materials. No family studies or parental testing results were provided.
PS3	Not met	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.	oncokb
PS4	Not met	No prevalence data available. The variant is absent from ClinVar, providing no evidence of enrichment in affected individuals versus controls.	clinvar
PS5	N/A	The variant is absent from ClinVar. No reputable source has reported this variant as pathogenic with evidence unavailable for independent evaluation.	clinvar
PM1	Not met	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.
PM2	Met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not assessed	No de novo data available. No confirmed de novo reports for this variant were identified in the case materials or literature.
PP1	Not assessed	No segregation data available. No family studies were provided in the case materials.
PP2	Not met	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.
PP3	Met	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.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype data was provided. The patient's clinical features are not available for comparison with CREBBP-associated Rubinstein-Taybi syndrome.
PP5	N/A	The variant is absent from ClinVar. No reputable source has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD (AF=0%), far below the BA1 threshold of >1% allele frequency in population databases.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD (AF=0%), far below the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not met	No functional studies demonstrating no damaging effect were identified. OncoKB reports an unknown oncogenic effect, which does not constitute evidence of normal function.	oncokb
BS4	Not assessed	No segregation data available. Lack of cosegregation with disease in affected families cannot be evaluated.
BP1	Not met	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.
BP2	Not assessed	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	No alternative molecular diagnosis data available. A different disease-causing variant explaining the phenotype was not reported.
BP6	N/A	The variant is absent from ClinVar. No reputable source has classified this variant as benign.	clinvar
BP7	N/A	This 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.	spliceai
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion in a non-repeat region.
PM3	N/A	No evidence for a recessive disorder; CREBBP-associated disease is autosomal dominant.
PM4	N/A	This is a substitution variant, not an in-frame deletion/insertion or stop-loss variant.

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