Variant classification summary

NM_004380.2:c.6436C>T

CREBBP · NP_004371.2:p.(Gln2146Ter) · NM_004380.2

GRCh37: chr16:3778612 G>A · GRCh38: chr16:3728611 G>A

Gene: CREBBP Transcript: NM_004380.2

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.(Gln2146Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 strong: the terminal-exon stop p.Gln2146Ter is predicted to escape nonsense-mediated decay.

2

PM2 supporting: the variant is absent from reported gnomAD datasets and available non-cancer subsets.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong criterion plus one supporting criterion does not reach a benign, likely benign, likely pathogenic, or pathogenic threshold, so the result is VUS.

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	Met	Met, strong: the exon 31 terminal-exon stop p.Gln2146Ter escapes NMD and removes 297 of 2443 amino acids, triggering the ClinGen SVI downgrade.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: parental genotypes, maternity or paternity confirmation, and a documented de novo result are absent for the affected proband.
PS3	Not assessed	Not assessed: no validated functional assay directly tested CREBBP p.Gln2146Ter.
PS4	Not assessed	Not assessed: no case-control enrichment, odds ratio, likelihood ratio, or qualifying aggregate case count was reported for NM_004380.2:c.6436C>T.	clinvar PMID:21390130
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and available non-cancer subsets, meeting the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: CREBBP-related Rubinstein-Taybi syndrome is autosomal dominant, so the recessive PM3 criterion does not apply.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no credible de novo report is provided, and the sole ClinVar submission records variant origin as unknown.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, pedigree, or familial variant-testing results are documented.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.6436C>T is a nonsense variant, whereas PP3 covers missense or splice-region/intronic variants in this group.
PP4	Not assessed	Not assessed: four Rubinstein-Taybi-associated features are listed, but no verified clinical case narrative establishes a highly specific phenotype for this exact variant.	clinvar
PP5	Not met	Not met: the exact variant has one single-submitter Pathogenic ClinVar assertion, but no expert-panel classification is present.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy carrier or homozygote is reported, and the variant is absent from gnomAD v2.1, v4.1, and available non-cancer subsets.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay directly tested CREBBP p.Gln2146Ter.
BS4	Not assessed	Not assessed: no unaffected carriers, non-segregating affected relatives, familial genotypes, or adequate relative phenotype data are documented.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second variant or cis/trans phase information is documented for c.6436C>T.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.6436C>T is a nonsense variant, whereas BP4 covers missense or splice-region/intronic variants in this group.
BP5	Not assessed	Not assessed: no alternate pathogenic variant or molecular diagnosis was provided to explain the presentation better than CREBBP.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the sole assertion is single-submitter Pathogenic.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004380.2:c.6436C>T in CREBBP is a nonsense substitution introducing a premature stop codon predicted to produce NP_004371.2:p.(Gln2146Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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