NM_004380.2:c.3215C>G

CREBBP · NP_004371.2:p.(Ser1072Cys) · NM_004380.2

GRCh37: chr16:3817756 G>C · GRCh38: chr16:3767755 G>C

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.(Ser1072Cys)

gnomAD AF

6.194796618632214e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004380.2:c.3215C>G (p.Ser1072Cys) is a missense variant in CREBBP. It is absent from ClinVar and absent from gnomAD v2.1, with a single heterozygous observation in gnomAD v4.1 at extremely low frequency (AF=6.19×10⁻⁷, 1/1,614,258).

This low population frequency meets PM2 at supporting strength.

Multiple computational predictors support a benign impact: REVEL score 0.046 (benign-leaning), BayesDel score -0.448 (predicted benign), and SpliceAI predicts no splice alteration (max Δ=0.00). This meets BP4 at supporting benign strength.

No variant-specific functional data, de novo observations, segregation data, or published case reports are available. No same-codon pathogenic comparators exist for PM5 or PS1. The variant is not in a mutational hotspot or characterized functional domain.

The variant does not qualify for PVS1 (missense, not a null variant). BP1 does not apply because missense variants are an established disease mechanism in CREBBP.

With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient for classification as pathogenic, likely pathogenic, likely benign, or benign. This variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines.

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.3215C>G, p.Ser1072Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense variants.	pvs1_generic_framework
PS1	Not met	No different nucleotide change at codon 1072 has been classified as pathogenic in ClinVar or published literature. The variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo observation has been reported for this variant. No publications or ClinVar submissions describe a de novo occurrence.
PS3	Not met	No variant-specific functional data exists. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence for this variant. No publications describe experimental characterization of p.Ser1072Cys or a systematically characterized range that includes residue 1072.	oncokb
PS4	Not met	No variant prevalence data in affected individuals versus controls. The variant is absent from ClinVar and has not been reported in any published case series or cohorts.	clinvar
PS5	Not met	No same amino acid change (p.Ser1072Cys) resulting from a different nucleotide substitution has been classified as pathogenic. The variant is absent from ClinVar entirely.	clinvar pm5_candidates
PM1	Not met	Residue 1072 is not in a statistically significant mutational hotspot (cancerhotspots.org: not significant). It lies in an inter-domain region between the KIX domain (~586-672) and the bromodomain (~1103-1175) and is not within a well-characterized functional domain with domain-level variant enrichment data.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes) and present at an extremely low frequency in gnomAD v4.1 (AF=6.19×10⁻⁷, 1/1,614,258 alleles, 0 homozygotes), well below the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4
PM5	Not met	No different pathogenic missense variant at codon 1072 has been identified. Automated PM5 candidate harvesting returned zero candidates at this residue.	pm5_candidates clinvar
PM6	Not met	No de novo observation has been reported for this variant. No publications or ClinVar submissions describe a de novo occurrence of c.3215C>G.
PP1	Not met	No segregation data is available for this variant. It has not been reported in any families or cosegregation studies.
PP2	Not met	While missense variants are a known disease mechanism in CREBBP, PP2 requires demonstrating a low rate of benign missense variation (e.g., via gnomAD missense Z-score or constraint metrics), which was not available in the case evidence.
PP3	Not met	Multiple in silico predictors support a benign impact: REVEL score 0.046 (below pathogenic threshold), BayesDel score -0.448 (predicted benign), SpliceAI max delta 0.00 (no splice impact). Computational evidence does not support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data is available for this adjudication. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5	Not met	The variant is absent from ClinVar. No reputable source or expert panel has classified this variant as pathogenic.	clinvar
BA1	Not met	The highest population allele frequency is 0.00133% (African/African American, gnomAD v4.1), well below the BA1 threshold of 1%.	gnomad_v4
BS1	Not met	The highest population allele frequency is 0.00133% (African/African American, gnomAD v4.1), well below the BS1 threshold of 0.3% for a dominant disorder.	gnomad_v4
BS2	Not met	A single allele was observed in gnomAD v4.1 (1/1,614,258), but this does not constitute confirmed observation in a healthy adult individual for a fully penetrant dominant disorder. The health status of the gnomAD individual is unknown.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no damaging effect for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.	oncokb
BS4	Not met	No segregation data is available for this variant. Lack of segregation in affected family members cannot be assessed.
BP1	Not met	Missense variants are a known disease mechanism in CREBBP. Among reported CREBBP RSTS variants, 24% are missense, indicating that missense variants are not an unexpected finding and BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant (for a recessive disorder) is available.
BP4	Met	Multiple lines of computational evidence support a benign impact: REVEL score 0.046 (well below pathogenic thresholds), BayesDel score -0.448 (predicted benign), and SpliceAI max delta 0.00 (no splice alteration predicted).	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in a case carrying this variant. No case-level diagnostic data is available.
BP6	Not met	The variant is absent from ClinVar. No reputable source or expert panel has classified this variant as benign.	clinvar
BP7	N/A	This is a missense variant (c.3215C>G, p.Ser1072Cys), not a synonymous (silent) variant. BP7 applies only to synonymous variants with no predicted splice impact.

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