rs3751845

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.6711C>T(p.Pro2237Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,612,204 control chromosomes in the GnomAD database, including 1,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 168 hom., cov: 32)

Exomes 𝑓: 0.015 ( 1069 hom. )

Consequence

CREBBP
NM_004380.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.81

Publications

20 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=-0.82).

BP6

Variant 16-3728336-G-A is Benign according to our data. Variant chr16-3728336-G-A is described in ClinVar as [Benign]. Clinvar id is 95066.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.81 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.6711C>T	p.Pro2237Pro	synonymous_variant	Exon 31 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10 link	c.6711C>T	p.Pro2237Pro	synonymous_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5		Q92793-1
CREBBP	ENST00000382070.7 link	c.6597C>T	p.Pro2199Pro	synonymous_variant	Exon 30 of 30	1		ENSP00000371502.3		Q92793-2

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4329

AN:

151916

Hom.:

168

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.0495

Gnomad AMR

AF:

0.0189

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.150

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00353

Gnomad OTH

AF:

0.0250

GnomAD2 exomes

AF:

0.0340

AC:

8186

AN:

240912

AF XY:

0.0363

show subpopulations

Gnomad AFR exome

AF:

0.0596

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.00670

Gnomad EAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.00151

Gnomad NFE exome

AF:

0.00403

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0147

AC:

21507

AN:

1460172

Hom.:

1069

Cov.:

AF XY:

0.0174

AC XY:

12622

AN XY:

726368

show subpopulations

African (AFR)

AF:

0.0607

AC:

2029

AN:

33442

American (AMR)

AF:

0.0116

AC:

519

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.00682

AC:

178

AN:

26090

East Asian (EAS)

AF:

0.125

AC:

4958

AN:

39638

South Asian (SAS)

AF:

0.106

AC:

9104

AN:

86122

European-Finnish (FIN)

AF:

0.00222

AC:

117

AN:

52770

Middle Eastern (MID)

AF:

0.0299

AC:

168

AN:

5614

European-Non Finnish (NFE)

AF:

0.00262

AC:

2916

AN:

1111616

Other (OTH)

AF:

0.0252

AC:

1518

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

1516

3033

4549

6066

7582

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0285

AC:

4336

AN:

152032

Hom.:

168

Cov.:

AF XY:

0.0299

AC XY:

2223

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0559

AC:

2319

AN:

41458

American (AMR)

AF:

0.0188

AC:

288

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00865

AC:

AN:

3470

East Asian (EAS)

AF:

0.150

AC:

775

AN:

5166

South Asian (SAS)

AF:

0.115

AC:

555

AN:

4806

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00353

AC:

240

AN:

67946

Other (OTH)

AF:

0.0252

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

197

394

592

789

986

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0117

Hom.:

Bravo

AF:

0.0299

Asia WGS

AF:

0.124

AC:

434

AN:

3476

EpiCase

AF:

0.00502

EpiControl

AF:

0.00387

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

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

- -

Inborn genetic diseases

Benign:1

May 06, 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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.74

(source)

DANN

Benign

0.61

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=78/22

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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rs3751845

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