16-3781229-G-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.1651C>A(p.Leu551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00973 in 1,613,964 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0076 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0099 ( 140 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 5.82

Publications

38 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=0.007070422).

BP6

Variant 16-3781229-G-T is Benign according to our data. Variant chr16-3781229-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95026.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=1, Benign=6, other=1}.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00764 (1163/152270) while in subpopulation EAS AF = 0.0129 (67/5186). AF 95% confidence interval is 0.0104. There are 13 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.1651C>A	p.Leu551Ile	missense_variant	Exon 7 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CREBBP	ENST00000262367.10 link	c.1651C>A	p.Leu551Ile	missense_variant	Exon 7 of 31	1	NM_004380.3	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7 link	c.1537C>A	p.Leu513Ile	missense_variant	Exon 6 of 30	1		ENSP00000371502.3	Q92793-2
CREBBP	ENST00000570939.2 link	c.256C>A	p.Leu86Ile	missense_variant	Exon 2 of 23	5		ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes

AF:

0.00765

AC:

1164

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.0617

Gnomad EAS

AF:

0.0131

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00844

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.0103

AC:

2584

AN:

251442

AF XY:

0.0109

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00908

Gnomad OTH exome

AF:

0.0134

GnomAD4 exome

AF:

0.00995

AC:

14541

AN:

1461694

Hom.:

140

Cov.:

AF XY:

0.0102

AC XY:

7437

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33478

American (AMR)

AF:

0.00555

AC:

248

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0583

AC:

1522

AN:

26118

East Asian (EAS)

AF:

0.0236

AC:

936

AN:

39692

South Asian (SAS)

AF:

0.0113

AC:

974

AN:

86248

European-Finnish (FIN)

AF:

0.00187

AC:

100

AN:

53408

Middle Eastern (MID)

AF:

0.0370

AC:

213

AN:

5762

European-Non Finnish (NFE)

AF:

0.00868

AC:

9656

AN:

1111872

Other (OTH)

AF:

0.0137

AC:

830

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

691

1382

2074

2765

3456

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00764

AC:

1163

AN:

152270

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41550

American (AMR)

AF:

0.00857

AC:

131

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0617

AC:

214

AN:

3468

East Asian (EAS)

AF:

0.0129

AC:

AN:

5186

South Asian (SAS)

AF:

0.0114

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00844

AC:

574

AN:

68020

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0116

Hom.:

Bravo

AF:

0.00774

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00205

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.0100

AC:

1214

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0136

EpiControl

AF:

0.0121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4Other:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 31, 2014

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

not provided

Benign:2

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 27, 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

Jan 21, 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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.47

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.79

T;T;T

MetaRNN

Benign

0.0071

T;T;T

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.2

L;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;N;.

REVEL

Uncertain

0.38

Sift

Benign

0.052

T;D;.

Sift4G

Benign

0.30

T;T;.

Polyphen

0.60

P;.;.

Vest4

0.23

MPC

1.3

ClinPred

0.017

GERP RS

5.5

PromoterAI

-0.0078

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.19

Mutation Taster

=69/31

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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16-3781229-G-T

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