Variant classification summary

NM_004380.2:c.7299C>A

CREBBP · NP_004371.2:p.(Asp2433Glu) · NM_004380.2

GRCh37: chr16:3777749 G>T · GRCh38: chr16:3727748 G>T

Gene: CREBBP Transcript: NM_004380.2

Final call

VUS

PM2 supporting

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.(Asp2433Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

VUS: a single supporting-strength criterion does not reach any pathogenic or benign combination threshold under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 combination rules require at minimum 1 PVS1+1PM, 1PS+1PM, 3PM, 2PM+2PP, or 1PM+4PP for Likely Pathogenic (or corresponding benign combinations for Likely Benign/Benign); with only PM2 supporting met and no other criteria met, none of these thresholds are reached, so the variant is classified as 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	Not applicable: this is a missense substitution, so no null-variant mechanism (e.g., nonsense-mediated decay) applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no known pathogenic variant producing the identical amino acid change p.Asp2433Glu was identified.	clinvar
PS2	Not assessed	Not assessed: no confirmed de novo occurrence with parental testing was documented for the proband.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay evidence for this variant was available.
PS4	Not assessed	Not assessed: no affected-case series or case-control enrichment evidence was available.
PM1	Not assessed	Not assessed: no residue-level domain or mutational-hotspot map covering codon 2433 was available.
PM2	Met	Met (supporting): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no pathogenic variant in trans or phase information was available.
PM4	N/A	Not applicable: missense substitution causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic missense variant at the same codon (2433) was identified for comparison.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no evidence of an assumed de novo origin was available.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no segregation data in affected or unaffected relatives were available.	generic_acmg_combination_rules
PP2	Not assessed	Not assessed: CREBBP disease is predominantly loss-of-function, and no missense constraint metric was available to confirm missense as a common mechanism.	pvs1_gene_context
PP3	Not met	Not met: REVEL score 0.597 falls in the indeterminate zone between the benign-supporting (<=0.290) and pathogenic-supporting (>=0.644) thresholds.	revel
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific phenotype comparison was supplied.
PP5	N/A	Not applicable: no ClinVar expert-panel pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: absent from population databases, so no allele frequency approaches a benign-alone threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no frequency exceeds the disease-prevalence threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations of unaffected adult carriers or homozygotes were available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay demonstrating normal or near-normal function was available.
BS4	Not assessed	Not assessed: no unaffected relatives carrying the variant or other non-segregation evidence were available.	generic_acmg_combination_rules
BP1	N/A	Not applicable: missense variants are an accepted CREBBP disease mechanism (24% of pathogenic findings in one cohort), not categorically benign.	pvs1_gene_context
BP2	Not assessed	Not assessed: no phase information or cis/trans placement relative to a pathogenic variant was available.
BP3	N/A	Not applicable: missense substitution is not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.597 exceeds the benign-supporting threshold of <=0.290.	revel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the phenotype was available.
BP6	N/A	Not applicable: no ClinVar expert-panel benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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