NM_004380.2:c.3780-2A>G

CREBBP · NP_004371.2:p.? · NM_004380.2

GRCh37: chr16:3799686 T>C · GRCh38: chr16:3749685 T>C

Gene: CREBBP Transcript: NM_004380.2

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.?

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_004380.2:c.3780-2A>G is a canonical splice acceptor variant (position -2 of intron 20) in CREBBP, a gene in which loss of function is an established mechanism for autosomal-dominant Rubinstein-Taybi syndrome.

Under the ClinGen SVI PVS1 decision tree (PMC6185798), this canonical ±1,2 splice variant meets PVS1 at very strong strength given the established CREBBP loss-of-function disease mechanism and absence of downgrade factors.

The variant is absent from gnomAD v4.1 (0/1,591,234 alleles) and gnomAD v2.1, meeting PM2 at moderate strength.

SpliceAI strongly predicts an effect on splicing (max delta 1.0, acceptor gain 1.0, acceptor loss 0.99), and BayesDel predicts a deleterious score of 0.66, consistent with a pathogenic splice-altering variant. These in silico predictions are not separately credited under PP3 per PVS1 stacking guidance.

The variant is absent from ClinVar, and no published case reports, functional studies, or de novo reports were identified for NM_004380.2:c.3780-2A>G in the available literature.

Overall, the variant meets 1 very strong criterion (PVS1) and 1 moderate criterion (PM2). No benign criteria are met. Per the ACMG/AMP 2015 scoring rubric (1 very strong + 1 moderate), this variant is classified as PATHOGENIC.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	This variant alters the canonical splice acceptor at position -2 of intron 20 in CREBBP (NM_004380.2:c.3780-2A>G). CREBBP loss of function is an established mechanism for Rubinstein-Taybi syndrome, an autosomal-dominant neurodevelopmental disorder. Under the ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with established LoF disease mechanisms are eligible for PVS1 at full strength. The variant is absent from population databases (gnomAD v4.1: 0/1,591,234 alleles), consistent with a pathogenic splice-altering variant under purifying selection. No downgrade factors are present: the affected exon is not absent from biologically relevant transcripts, and population LoF constraint data does not suggest tolerance.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment gnomad_v4 gnomad_v2
PS1	N/A	This is a canonical splice site variant, not a missense change. PS1 requires the same amino acid change as a previously established pathogenic variant, which is not applicable to splice-altering variants.
PS2	Not met	No de novo data are available for this variant. No published case reports or clinical submissions document a de novo occurrence confirmed by parental testing.
PS3	Not met	No functional data exist for NM_004380.2:c.3780-2A>G or a systematically characterized range that includes this variant. No experimental studies (saturation mutagenesis, tiling screen, or systematic truncation series) have characterized the intron 20 splice acceptor region. Domain-level inference from gene-level functional studies does not satisfy PS3 requirements.
PS4	Not met	This variant is absent from ClinVar and has not been reported in any published case series or cohort studies. No case-control data or odds-ratio statistics are available to support statistically significant enrichment in affected individuals.	clinvar
PS5	N/A	PS5 requires a distinct pathogenic variant at the same amino acid position. This is a canonical splice site variant with no defined amino acid position, making PS5 inapplicable.
PM1	Not met	While CREBBP contains well-characterized functional domains (KIX, bromodomain, HAT/KAT11), the specific region affected by loss of the intron 20 splice acceptor has not been identified as a mutational hotspot or critical functional domain with limited benign variation. No cancerhotspots.org significance was found for this residue. Without domain-specific evidence demonstrating that this region is intolerant to variation, PM1 cannot be applied.
PM2	Met	This variant is absent from large population databases. In gnomAD v4.1, it is observed at 0/1,591,234 alleles (AF=0.000%), including 0/74656 African/African American alleles. It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Under generic ACMG/AMP guidelines, absence from population databases at an allele frequency well below 0.1% meets PM2 at moderate strength.	gnomad_v4 gnomad_v2 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This is a canonical splice site variant (c.3780-2A>G) with no defined protein consequence, making PM5 structurally inapplicable. The pm5_candidates pipeline confirmed no eligible same-residue comparators.	pm5_candidates
PM6	Not met	No de novo occurrence has been documented for this variant. The published literature on CREBBP-related Rubinstein-Taybi syndrome describes splice-site variants generally but does not report NM_004380.2:c.3780-2A>G specifically as a de novo event.
PP1	Not met	No co-segregation data are available for this variant. No family studies have been published demonstrating co-segregation with Rubinstein-Taybi syndrome or any other CREBBP-related phenotype.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a canonical splice site variant, not a missense change.
PP3	Not met	Multiple in silico tools predict a deleterious effect (SpliceAI max delta 1.0, DS_AG=1.0, DS_AL=0.99; BayesDel 0.66). However, under PMC6185798 guidance, computational splice prediction evidence should not be double-counted when PVS1 has already been applied for a canonical splice variant. The in silico evidence supporting splice disruption is already captured in the PVS1 assessment.	spliceai bayesdel
PP4	Not met	No phenotype specificity data are available for this variant. While CREBBP variants are associated with Rubinstein-Taybi syndrome, no clinical data confirm that this specific proband's phenotype is highly specific for CREBBP-related disease.
PP5	Not met	This variant is absent from ClinVar. No expert panel or reputable clinical laboratory has submitted a classification for NM_004380.2:c.3780-2A>G, so there is no external classification to credit under PP5.	clinvar
BA1	Not met	This variant is absent from gnomAD v4.1 (0/1,591,234 alleles, AF=0.000%), far below the BA1 threshold of >1%. It does not meet the population frequency requirement for a stand-alone benign classification.	gnomad_v4
BS1	Not met	This variant is absent from gnomAD (AF=0.000%), far below the BS1 threshold of >0.3%. The population frequency data do not support a benign interpretation.	gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual with full penetrance expected at an early age. No such observation exists for NM_004380.2:c.3780-2A>G. The variant is entirely absent from population databases and no healthy control carriers have been reported.	gnomad_v4
BS3	Not met	No functional studies have assessed NM_004380.2:c.3780-2A>G. No experimental data demonstrate that this splice variant has no deleterious effect on protein function or splicing.
BS4	Not met	No lack of segregation data are available. No family studies have been performed to assess whether the variant fails to segregate with disease in affected families.
BP1	N/A	BP1 applies to missense variants in genes where a truncating mechanism is primarily causative. This is a canonical splice site variant predicted to cause aberrant splicing and likely loss of function, not a missense change with an alternative molecular basis.
BP2	Not met	No observation of this variant in trans with a known pathogenic CREBBP variant has been reported. In the absence of such data, BP2 cannot be applied.
BP4	Not met	Multiple lines of computational evidence predict a deleterious effect. SpliceAI indicates strong splice disruption (max delta 1.0; DS_AG=1.0, DS_AL=0.99) and BayesDel predicts a deleterious score of 0.66. These predictions are inconsistent with a benign interpretation and do not support BP4.	spliceai bayesdel
BP5	Not met	No data are available demonstrating that this variant has been observed in a case with a definitive alternate molecular basis for disease. BP5 requires a specific alternative explanation for the observed phenotype, which has not been established.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified NM_004380.2:c.3780-2A>G as benign or likely benign, so there is no external benign classification to credit under BP6.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This is a canonical splice site variant (c.3780-2A>G), not a synonymous variant, and splice prediction algorithms predict a strong deleterious effect.

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