rs3025694

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004380.3(CREBBP):c.2784G>A(p.Pro928Pro) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.47

Publications

15 publications found

Variant links:

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]

CREBBP Gene-Disease associations (from GenCC):

Rubinstein-Taybi syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
Rubinstein-Taybi syndrome due to CREBBP mutations
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
Menke-Hennekam syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

CREBBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.2784G>A	p.Pro928Pro	synonymous_variant	Exon 14 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CREBBP	ENST00000262367.10 link	c.2784G>A	p.Pro928Pro	synonymous_variant	Exon 14 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7 link	c.2670G>A	p.Pro890Pro	synonymous_variant	Exon 13 of 30	1		ENSP00000371502.3
CREBBP	ENST00000570939.2 link	c.1389G>A	p.Pro463Pro	synonymous_variant	Exon 9 of 23	5		ENSP00000461002.2
CREBBP	ENST00000573672.1 link	n.38G>A		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3492

AN:

152010

Hom.:

167

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0346

AC:

8686

AN:

251184

AF XY:

0.0378

show subpopulations

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 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.:

AF XY:

0.0180

AC XY:

13062

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0352

AC:

1177

AN:

33478

American (AMR)

AF:

0.0101

AC:

451

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00589

AC:

154

AN:

26136

East Asian (EAS)

AF:

0.168

AC:

6670

AN:

39700

South Asian (SAS)

AF:

0.111

AC:

9614

AN:

86252

European-Finnish (FIN)

AF:

0.00219

AC:

117

AN:

53344

Middle Eastern (MID)

AF:

0.0237

AC:

136

AN:

5742

European-Non Finnish (NFE)

AF:

0.00213

AC:

2364

AN:

1111996

Other (OTH)

AF:

0.0247

AC:

1492

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1410

2820

4230

5640

7050

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0230

AC:

3493

AN:

152126

Hom.:

168

Cov.:

AF XY:

0.0256

AC XY:

1902

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0324

AC:

1345

AN:

41498

American (AMR)

AF:

0.0158

AC:

242

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.195

AC:

1005

AN:

5162

South Asian (SAS)

AF:

0.117

AC:

564

AN:

4814

European-Finnish (FIN)

AF:

0.00189

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00307

AC:

209

AN:

67988

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

151

302

452

603

754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00912

Hom.:

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Rubinstein-Taybi syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 16, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

-0.53

CADD

Benign

0.44

(source)

DANN

Benign

0.58

PhyloP100

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over