chr16-3729328-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004380.3(CREBBP):c.5719G>A(p.Ala1907Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,572,556 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 6 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:12

Conservation

PhyloP100: 0.353

Publications

6 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009790987).

BP6

Variant 16-3729328-C-T is Benign according to our data. Variant chr16-3729328-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95056.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (185/151664) while in subpopulation SAS AF = 0.00188 (9/4794). AF 95% confidence interval is 0.00157. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 185 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004380.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.5719G>A	p.Ala1907Thr	missense	Exon 31 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.5605G>A	p.Ala1869Thr	missense	Exon 30 of 30	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.5719G>A	p.Ala1907Thr	missense	Exon 31 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.5605G>A	p.Ala1869Thr	missense	Exon 30 of 30	ENSP00000371502.3

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

151546

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000510

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00183

Gnomad OTH

AF:

0.00289

GnomAD2 exomes

AF:

0.00154

AC:

288

AN:

186422

AF XY:

0.00172

show subpopulations

Gnomad AFR exome

AF:

0.000350

Gnomad AMR exome

AF:

0.000935

Gnomad ASJ exome

AF:

0.000781

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00338

GnomAD4 exome

AF:

0.00175

AC:

2490

AN:

1420892

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1287

AN XY:

704458

show subpopulations

African (AFR)

AF:

0.000641

AC:

AN:

32786

American (AMR)

AF:

0.00114

AC:

AN:

38640

Ashkenazi Jewish (ASJ)

AF:

0.000862

AC:

AN:

25522

East Asian (EAS)

AF:

0.00

AC:

AN:

37846

South Asian (SAS)

AF:

0.00293

AC:

244

AN:

83182

European-Finnish (FIN)

AF:

0.000218

AC:

AN:

41338

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00179

AC:

1964

AN:

1096868

Other (OTH)

AF:

0.00225

AC:

133

AN:

59156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

164

328

493

657

821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<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:

0.00122

AC:

185

AN:

151664

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

41334

American (AMR)

AF:

0.00125

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.00188

AC:

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10536

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00183

AC:

124

AN:

67854

Other (OTH)

AF:

0.00286

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00146

Hom.:

Bravo

AF:

0.00131

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00188

AC:

ExAC

AF:

0.00142

AC:

171

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Dec 21, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 24, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23891399, 27884173, 22591219)

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CREBBP: PP2, BP4, BS1, BS2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:3

Apr 28, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 05, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 19, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Rubinstein-Taybi syndrome due to CREBBP mutations

Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CREBBP-related disorder

Benign:1

May 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Inborn genetic diseases

Benign:1

Jan 10, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Benign

7.7

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.39

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0098

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.46

PhyloP100

0.35

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.63

REVEL

Uncertain

0.50

Sift

Benign

0.51

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.088

MVP

0.97

MPC

1.3

ClinPred

0.00087

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.041

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over