NM_004380.3:c.6621A>G

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.6621A>G(p.Gln2207Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,396 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 33 hom., cov: 32)

Exomes 𝑓: 0.012 ( 267 hom. )

Consequence

CREBBP
NM_004380.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0870

Publications

3 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=-0.75).

BP6

Variant 16-3728426-T-C is Benign according to our data. Variant chr16-3728426-T-C is described in ClinVar as Benign. ClinVar VariationId is 95063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.087 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3 link	c.6621A>G	p.Gln2207Gln	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.6621A>G	p.Gln2207Gln	synonymous_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7 link	c.6507A>G	p.Gln2169Gln	synonymous_variant	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1914

AN:

151710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00964

Gnomad ASJ

AF:

0.0476

Gnomad EAS

AF:

0.0116

Gnomad SAS

AF:

0.0564

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00718

Gnomad OTH

AF:

0.0159

GnomAD2 exomes

AF:

0.0157

AC:

3847

AN:

245396

AF XY:

0.0178

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.00576

Gnomad ASJ exome

AF:

0.0468

Gnomad EAS exome

AF:

0.0156

Gnomad FIN exome

AF:

0.00131

Gnomad NFE exome

AF:

0.00830

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0120

AC:

17489

AN:

1460568

Hom.:

267

Cov.:

AF XY:

0.0133

AC XY:

9696

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.0171

AC:

573

AN:

33448

American (AMR)

AF:

0.00600

AC:

268

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.0465

AC:

1214

AN:

26130

East Asian (EAS)

AF:

0.0211

AC:

836

AN:

39658

South Asian (SAS)

AF:

0.0519

AC:

4472

AN:

86140

European-Finnish (FIN)

AF:

0.00186

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.0316

AC:

182

AN:

5758

European-Non Finnish (NFE)

AF:

0.00798

AC:

8867

AN:

1111270

Other (OTH)

AF:

0.0162

AC:

978

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1403

2807

4210

5614

7017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.0126

AC:

1914

AN:

151828

Hom.:

Cov.:

AF XY:

0.0130

AC XY:

968

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.0178

AC:

733

AN:

41264

American (AMR)

AF:

0.00963

AC:

147

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

165

AN:

3466

East Asian (EAS)

AF:

0.0114

AC:

AN:

5156

South Asian (SAS)

AF:

0.0566

AC:

272

AN:

4804

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00718

AC:

488

AN:

67940

Other (OTH)

AF:

0.0152

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

196

295

393

491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0131

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 18, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.029

(source)

DANN

Benign

0.23

PhyloP100

-0.087

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