rs3025694

chr16-3770666-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004380.3(CREBBP):c.2784G>A(p.Pro928=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,890 control chromosomes in the GnomAD database, including 1,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (168 hom., cov: 31)
  • Exomes 𝑓: 0.015 (1345 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.47

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-3770666-C-T is Benign according to our data. Variant chr16-3770666-C-T is described in ClinVar as [Benign]. Clinvar id is 158350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.2784G>A	p.Pro928=	synonymous_variant	14/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.2784G>A	p.Pro928=	synonymous_variant	14/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.2670G>A	p.Pro890=	synonymous_variant	13/30	1
CREBBP	ENST00000570939.2	c.1389G>A	p.Pro463=	synonymous_variant	9/23	5
CREBBP	ENST00000573672.1	n.38G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3492 AN: 152010 Hom.: 167 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0346 AC: 8686 AN: 251184 Hom.: 620 AF XY: 0.0378 AC XY: 5133 AN XY: 135804

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.203

Gnomad SAS exome AF: 0.114

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0152 AC: 22175 AN: 1461764 Hom.: 1345 Cov.: 33 AF XY: 0.0180 AC XY: 13062 AN XY: 727200

Gnomad4 AFR exome AF: 0.0352

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0230 AC: 3493 AN: 152126 Hom.: 168 Cov.: 31 AF XY: 0.0256 AC XY: 1902 AN XY: 74372

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00307

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00858 Hom.: 8

Bravo AF: 0.0237

Asia WGS AF: 0.141 AC: 489 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00350

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	0.44
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs3025694; hg19: chr16-3820667; COSMIC: COSV52117511; COSMIC: COSV52117511;