NM_004380.3:c.939T>C

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.939T>C(p.Asp313Asp) 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

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.63

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=-0.63).

BP6

Variant 16-3810639-A-G is Benign according to our data. Variant chr16-3810639-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.939T>C	p.Asp313Asp	synonymous_variant	Exon 3 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CREBBP	ENST00000262367.10 link	c.939T>C	p.Asp313Asp	synonymous_variant	Exon 3 of 31	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 link	c.939T>C	p.Asp313Asp	synonymous_variant	Exon 3 of 30	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000635899.1 link	n.*81T>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0796

AC:

12076

AN:

151696

Hom.:

1348

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0299

AC:

7510

AN:

251464

AF XY:

0.0250

show subpopulations

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 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.:

AF XY:

0.0167

AC XY:

12142

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.264

AC:

8827

AN:

33474

American (AMR)

AF:

0.0217

AC:

970

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

1508

AN:

26136

East Asian (EAS)

AF:

0.0218

AC:

866

AN:

39700

South Asian (SAS)

AF:

0.0119

AC:

1029

AN:

86246

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53420

Middle Eastern (MID)

AF:

0.0453

AC:

258

AN:

5698

European-Non Finnish (NFE)

AF:

0.00909

AC:

10106

AN:

1112008

Other (OTH)

AF:

0.0316

AC:

1910

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

1438

2875

4313

5750

7188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.0798

AC:

12117

AN:

151812

Hom.:

1354

Cov.:

AF XY:

0.0759

AC XY:

5630

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.252

AC:

10406

AN:

41298

American (AMR)

AF:

0.0399

AC:

608

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.0614

AC:

213

AN:

3470

East Asian (EAS)

AF:

0.0124

AC:

AN:

5144

South Asian (SAS)

AF:

0.0129

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00883

AC:

600

AN:

67968

Other (OTH)

AF:

0.0678

AC:

143

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

457

914

1372

1829

2286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0405

Hom.:

953

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

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

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. -

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

-0.63

CADD

Benign

8.6

(source)

DANN

Benign

0.79

PhyloP100

2.6

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