rs1555471323
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_004380.3(CREBBP):c.5694_5703del(p.Ser1898ArgfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
CREBBP
NM_004380.3 frameshift
NM_004380.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.91
Genes affected
CREBBP (HGNC:2348): (CREB binding protein) This gene is ubiquitously expressed and is involved in the transcriptional coactivation of many different transcription factors. First isolated as a nuclear protein that binds to cAMP-response element binding protein (CREB), this gene is now known to play critical roles in embryonic development, growth control, and homeostasis by coupling chromatin remodeling to transcription factor recognition. The protein encoded by this gene has intrinsic histone acetyltransferase activity and also acts as a scaffold to stabilize additional protein interactions with the transcription complex. This protein acetylates both histone and non-histone proteins. This protein shares regions of very high sequence similarity with protein p300 in its bromodomain, cysteine-histidine-rich regions, and histone acetyltransferase domain. Mutations in this gene cause Rubinstein-Taybi syndrome (RTS). Chromosomal translocations involving this gene have been associated with acute myeloid leukemia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 45 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-3729343-TCTGGGGTGTG-T is Pathogenic according to our data. Variant chr16-3729343-TCTGGGGTGTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 458203.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CREBBP | NM_004380.3 | c.5694_5703del | p.Ser1898ArgfsTer14 | frameshift_variant | 31/31 | ENST00000262367.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CREBBP | ENST00000262367.10 | c.5694_5703del | p.Ser1898ArgfsTer14 | frameshift_variant | 31/31 | 1 | NM_004380.3 | P1 | |
CREBBP | ENST00000382070.7 | c.5580_5589del | p.Ser1860ArgfsTer14 | frameshift_variant | 30/30 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rubinstein-Taybi syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 17, 2017 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with a CREBBP-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CREBBP (p.Ser1898Argfs*14). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 545 amino acids of the CREBBP protein. Two different truncations downstream of this variant (p.Ser2015Alafs*25 and  p.Gln2022Argfs*16) have been determined to be pathogenic (PMID: 17052327). This suggests that deletion of this region of the CREBBP protein is causative of disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at