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NM_004380.2:c.6436C>T
p.Gln2146Ter · CREBBP
ACMG/AMP
0%
complete
Final classification
VUS
PVS1PM2
CREBBP
c.6436C>T
p.Gln2146Ter
nonsense · exon 31
Gene context NCBI Gene ↗ OncoKB ↗

CREBBP encodes a transcriptional co-activator with intrinsic histone acetyltransferase activity that couples chromatin remodeling to gene transcription and supports normal embryonic development, growth control, and cellular homeostasis. Inherited mutations in this gene cause Rubinstein-Taybi syndrome, a developmental disorder marked by distinctive facial and digit abnormalities along with neurological deficits. CREBBP acts as a tumor suppressor in cancer: it is disrupted by chromosomal translocations in acute myeloid leukemia, and somatic alterations occur across leukemias, lymphomas, and solid tumors such as small-cell lung, bladder, and squamous carcinomas.

This variant

This CREBBP truncating variant affects a gene whose inherited loss-of-function mutations cause Rubinstein-Taybi syndrome and whose transcriptional co-activator activity supports normal development and cellular homeostasis.

Transcript
NM_004380.2
HGVS · transcript:coding
NM_004380.2:c.6436C>T
GRCh38
chr16:3728611 G>A
GRCh37
chr16:3778612 G>A
VUS: PVS1 (strong) plus PM2 (supporting) do not meet a generic ACMG/AMP pathogenic or likely pathogenic combination threshold.
Classification rationale
PVS1PM2 VUS
CREBBP c.6436C>T nonsense · exon 31

PVS1 strong: the terminal-exon stop p.Gln2146Ter is predicted to escape nonsense-mediated decay. PM2 supporting: the variant is absent from reported gnomAD datasets and available non-cancer subsets.

PVS1 + PM2 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_004380.2 · variants mapped to exon structure
CREBBP NM_004380.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
PVS1 strong Pathogenic
Met, strong: the exon 31 terminal-exon stop p.Gln2146Ter escapes NMD and removes 297 of 2443 amino acids, triggering the ClinGen SVI downgrade.
The normalized variant is NM_004380.2:c.6436C>T, a nonsense change yielding NP_004371.2:p.(Gln2146Ter).Variant Validator identifies NM_004380.2 as the RefSeq-selected CREBBP transcript and places the variant in exon 31, the terminal coding exon.The exon map gives the terminal exon coding interval as c.5173-c.*2664, encompassing c.6436.
pvs1_generic_framework ↗
PM2 supporting Pathogenic
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 v2.1 reports the variant as absent.gnomAD v4.1 reports the variant as absent.The available gnomAD v2.1 non-cancer and v3.1 non-cancer records also report the variant as absent.
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
Assessed · not applied · 5 not met · 10 not assessed
Pathogenic
PS2 Not assessed: parental genotypes, maternity or paternity confirmation, and a documented de novo result are absent for the affected proband.
PS3 Not assessed: no validated functional assay directly tested CREBBP p.Gln2146Ter.
PS4 Not assessed: no case-control enrichment, odds ratio, likelihood ratio, or qualifying aggregate case count was reported for NM_004380.2:c.6436C>T.
PM6 Not assessed: no credible de novo report is provided, and the sole ClinVar submission records variant origin as unknown.
PP1 Not assessed: no affected relatives, informative meioses, pedigree, or familial variant-testing results are documented.
PP4 Not assessed: four Rubinstein-Taybi-associated features are listed, but no verified clinical case narrative establishes a highly specific phenotype for this exact variant.
PP5 Not met: the exact variant has one single-submitter Pathogenic ClinVar assertion, but no expert-panel classification is present.
Benign
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the generic BA1 allele-frequency threshold of 0.05.
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the generic BS1 allele-frequency threshold of 0.01.
BS2 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.
BS3 Not assessed: no validated benign functional assay directly tested CREBBP p.Gln2146Ter.
BS4 Not assessed: no unaffected carriers, non-segregating affected relatives, familial genotypes, or adequate relative phenotype data are documented.
BP2 Not assessed: no second variant or cis/trans phase information is documented for c.6436C>T.
BP5 Not assessed: no alternate pathogenic variant or molecular diagnosis was provided to explain the presentation better than CREBBP.
BP6 Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present; the sole assertion is single-submitter Pathogenic.
N/A · 11 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 694717)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.66.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105864263, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 2 further PMIDs triaged but not cited — see Sources & references.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
PMID 25741868 ↗ · Richards S et al. · 2015 May CLINVAR · functional
Found
The supplied generic ClinGen SVI PM2 recommendation uses allele frequency <=0.0001 for supporting strength (PMID:25741868).
Applied to
→PM2 supporting
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 2 PMIDs not cited in assessment
21390130 ↗ CREBBP mutations in relapsed acute lymphoblastic leukaemia. ONCOKB
20301699 ↗ Rubinstein-Taybi Syndrome. CLINVAR