rs3025702

Positions:

• chr16-3810639-A-G

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.939T>C​(p.Asp313=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,613,606 control chromosomes in the GnomAD database, including 2,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (1354 hom., cov: 31)
  • Exomes 𝑓: 0.017 (1369 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.63

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=-0.63).
• BP6: Variant 16-3810639-A-G is Benign according to our data. Variant chr16-3810639-A-G is described in ClinVar as [Benign]. Clinvar id is 95070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.939T>C	p.Asp313=	synonymous_variant	3/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.939T>C	p.Asp313=	synonymous_variant	3/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.939T>C	p.Asp313=	synonymous_variant	3/30	1

Frequencies

GnomAD3 genomes AF: 0.0796 AC: 12076 AN: 151696 Hom.: 1348 Cov.: 31

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.0126

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00133

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00883

Gnomad OTH AF: 0.0685

GnomAD3 exomes AF: 0.0299 AC: 7510 AN: 251464 Hom.: 585 AF XY: 0.0250 AC XY: 3404 AN XY: 135900

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0580

Gnomad EAS exome AF: 0.0174

Gnomad SAS exome AF: 0.0119

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00970

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0175 AC: 25574 AN: 1461794 Hom.: 1369 Cov.: 31 AF XY: 0.0167 AC XY: 12142 AN XY: 727192

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.0577

Gnomad4 EAS exome AF: 0.0218

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00909

Gnomad4 OTH exome AF: 0.0316

GnomAD4 genome AF: 0.0798 AC: 12117 AN: 151812 Hom.: 1354 Cov.: 31 AF XY: 0.0759 AC XY: 5630 AN XY: 74200

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0614

Gnomad4 EAS AF: 0.0124

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00133

Gnomad4 NFE AF: 0.00883

Gnomad4 OTH AF: 0.0678

Alfa AF: 0.0339 Hom.: 546

Bravo AF: 0.0910

Asia WGS AF: 0.0350 AC: 121 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0129

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.6
DANN	Benign	0.79
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: rs3025702; hg19: chr16-3860640;