16-3729218-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_004380.3(CREBBP):c.5829G>A(p.Pro1943Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,525,842 control chromosomes in the GnomAD database, including 6 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 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

CREBBP
NM_004380.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -5.26

Publications

1 publications found

Variant links:

COSMIC-nc: COSV106054294

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 16-3729218-C-T is Benign according to our data. Variant chr16-3729218-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158389.

BP7

Synonymous conserved (PhyloP=-5.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00112 (168/150216) while in subpopulation SAS AF = 0.00445 (21/4716). AF 95% confidence interval is 0.00298. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.5829G>A	p.Pro1943Pro	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.5829G>A	p.Pro1943Pro	synonymous_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5		Q92793-1
CREBBP	ENST00000382070.7 link	c.5715G>A	p.Pro1905Pro	synonymous_variant	Exon 30 of 30	1		ENSP00000371502.3		Q92793-2

Frequencies

GnomAD3 genomes

AF:

0.00112

AC:

168

AN:

150106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000172

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000133

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00445

Gnomad FIN

AF:

0.00424

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.00143

AC:

187

AN:

130350

AF XY:

0.00183

show subpopulations

Gnomad AFR exome

AF:

0.000312

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000127

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00401

Gnomad NFE exome

AF:

0.00178

Gnomad OTH exome

AF:

0.000499

GnomAD4 exome

AF:

0.00193

AC:

2653

AN:

1375626

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

1366

AN XY:

678032

show subpopulations

African (AFR)

AF:

0.000255

AC:

AN:

31396

American (AMR)

AF:

0.0000282

AC:

AN:

35466

Ashkenazi Jewish (ASJ)

AF:

0.0000804

AC:

AN:

24878

East Asian (EAS)

AF:

0.00

AC:

AN:

35636

South Asian (SAS)

AF:

0.00341

AC:

268

AN:

78544

European-Finnish (FIN)

AF:

0.00440

AC:

149

AN:

33828

Middle Eastern (MID)

AF:

0.000988

AC:

AN:

4050

European-Non Finnish (NFE)

AF:

0.00201

AC:

2159

AN:

1074412

Other (OTH)

AF:

0.00108

AC:

AN:

57416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

128

256

384

512

640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00112

AC:

168

AN:

150216

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

AN XY:

73312

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

40812

American (AMR)

AF:

0.000132

AC:

AN:

15110

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5088

South Asian (SAS)

AF:

0.00445

AC:

AN:

4716

European-Finnish (FIN)

AF:

0.00424

AC:

AN:

10370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

67420

Other (OTH)

AF:

0.000483

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00105

Hom.:

Bravo

AF:

0.000737

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 29, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CREBBP: BP4, BP7 -

not specified

Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CREBBP-related disorder

Benign:1

Jul 13, 2021

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). -

Rubinstein-Taybi syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 03, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

5.8

(source)

DANN

Benign

0.70

PhyloP100

-5.3

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over