rs149961222

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004380.3(CREBBP):c.895A>G(p.Ser299Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

CREBBP
NM_004380.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 2.34

Publications

8 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: Illumina, ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008075535).

BP6

Variant 16-3810683-T-C is Benign according to our data. Variant chr16-3810683-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 133934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000755 (115/152228) while in subpopulation AFR AF = 0.00262 (109/41552). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 115 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.895A>G	p.Ser299Gly	missense	Exon 3 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.895A>G	p.Ser299Gly	missense	Exon 3 of 30	NP_001073315.1	Q92793-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.895A>G	p.Ser299Gly	missense	Exon 3 of 31	ENSP00000262367.5	Q92793-1
CREBBP	ENST00000382070.7	TSL:1	c.895A>G	p.Ser299Gly	missense	Exon 3 of 30	ENSP00000371502.3	Q92793-2
CREBBP	ENST00000635899.1	TSL:5	n.*37A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

116

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251454

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00239

AC:

AN:

33474

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.0000828

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000755

AC:

115

AN:

152228

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41552

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000227

Hom.:

Bravo

AF:

0.000722

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CREBBP-related disorder (1)

Inborn genetic diseases (1)

Rubinstein-Taybi syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.63

M_CAP

Benign

0.018

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.4

PhyloP100

2.3

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.040

Sift4G

Benign

0.31

Polyphen

0.73

Vest4

0.077

MVP

0.82

MPC

0.14

ClinPred

0.017

GERP RS

4.2

Varity_R

0.066

gMVP

0.17

Mutation Taster

=80/20

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over