16-3729209-TG-TGG

Position:

• chr16-3729209-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_004380.3(CREBBP):​c.5837dupC​(p.Pro1947fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000195 in 205,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CREBBP NM_004380.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.82

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 Pathogenic. Variant got 14 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-3729209-T-TG is Pathogenic according to our data. Variant chr16-3729209-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 210783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.5837dupC	p.Pro1947fs	frameshift_variant	31/31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.5837dupC	p.Pro1947fs	frameshift_variant	31/31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5723dupC	p.Pro1909fs	frameshift_variant	30/30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000195 AC: 4 AN: 205486 Hom.: 0 Cov.: 38 AF XY: 0.00000926 AC XY: 1 AN XY: 108030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000427

Gnomad4 FIN exome AF: 0.000173

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rubinstein-Taybi syndrome due to CREBBP mutations Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Feb 01, 2024	ACMG Criteria: PP5, PM2, PS2, PVS1; Variant was found in heterozygous state -
Pathogenic, no assertion criteria provided	clinical testing	Wessex Regional Genetics Laboratory, Salisbury District Hospital	Nov 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Aug 05, 2024	- -

CREBBP-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This frameshift variant is found in the last exon of CREBBP and it is therefore predicted to escape nonsense-mediated mRNA decay (NMD). However, frameshift variants located downstream of this variant have been reported as disease-causing variants in the literature (PMID: 25388907, 32827181). This variant has been previously reported as a heterozygous change in patients with Rubinstein-Taybi syndrome (PMID: 25388907, 27342041, 32827181). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.5837dup (p.Pro1947ThrfsTer19) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783507; hg19: chr16-3779210;