rs797045500

chr16-3728629-GCAGGCTGGGCTGCTGGTGCATGC-Gchr16-3728629-GCAGGCTGGGCTGCTGGTGCATGC-GCAGGCTGGGCTGCTGGTGCATGCCAGGCTGGGCTGCTGGTGCATGC

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_004380.3(CREBBP):c.6395_6417del(p.Gly2132AlafsTer201) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREBBP NM_004380.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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 8 pathogenic variants in the truncated region.
• PP5: Variant 16-3728629-GCAGGCTGGGCTGCTGGTGCATGC-G is Pathogenic according to our data. Variant chr16-3728629-GCAGGCTGGGCTGCTGGTGCATGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 694795.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.6395_6417del	p.Gly2132AlafsTer201	frameshift_variant	31/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.6395_6417del	p.Gly2132AlafsTer201	frameshift_variant	31/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.6281_6303del	p.Gly2094AlafsTer201	frameshift_variant	30/30	1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Wessex Regional Genetics Laboratory, Salisbury District Hospital

Nov 05, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045500; hg19: chr16-3778630;