rs3025694

Variant names:

• chr16-3770666-C-T
• rs3025694
• NM_004380.3:c.2784G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004380.3(CREBBP):​c.2784G>A​(p.Pro928Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,613,890 control chromosomes in the GnomAD database, including 1,513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (168 hom., cov: 31)
  • Exomes 𝑓: 0.015 (1345 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.47
• Publications: 15 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 16-3770666-C-T is Benign according to our data. Variant chr16-3770666-C-T is described in ClinVar as Benign. ClinVar VariationId is 158350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.47 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

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.2784G>A	p.Pro928Pro	synonymous	Exon 14 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.2670G>A	p.Pro890Pro	synonymous	Exon 13 of 30	NP_001073315.1	Q92793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.2784G>A	p.Pro928Pro	synonymous	Exon 14 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.2670G>A	p.Pro890Pro	synonymous	Exon 13 of 30	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000570939.2	TSL:5	c.1389G>A	p.Pro463Pro	synonymous	Exon 9 of 23	ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3492 AN: 152010 Hom.: 167 Cov.: 31

Gnomad AFR AF: 0.0324

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00307

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0346 AC: 8686 AN: 251184 AF XY: 0.0378

Gnomad AFR exome AF: 0.0323

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0152 AC: 22175 AN: 1461764 Hom.: 1345 Cov.: 33 AF XY: 0.0180 AC XY: 13062 AN XY: 727200

African (AFR) AF: 0.0352 AC: 1177 AN: 33478

American (AMR) AF: 0.0101 AC: 451 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 154 AN: 26136

East Asian (EAS) AF: 0.168 AC: 6670 AN: 39700

South Asian (SAS) AF: 0.111 AC: 9614 AN: 86252

European-Finnish (FIN) AF: 0.00219 AC: 117 AN: 53344

Middle Eastern (MID) AF: 0.0237 AC: 136 AN: 5742

European-Non Finnish (NFE) AF: 0.00213 AC: 2364 AN: 1111996

Other (OTH) AF: 0.0247 AC: 1492 AN: 60392

GnomAD4 genome AF: 0.0230 AC: 3493 AN: 152126 Hom.: 168 Cov.: 31 AF XY: 0.0256 AC XY: 1902 AN XY: 74372

African (AFR) AF: 0.0324 AC: 1345 AN: 41498

American (AMR) AF: 0.0158 AC: 242 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3470

East Asian (EAS) AF: 0.195 AC: 1005 AN: 5162

South Asian (SAS) AF: 0.117 AC: 564 AN: 4814

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10598

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 67988

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.00912 Hom.: 8

Bravo AF: 0.0237

Asia WGS AF: 0.141 AC: 489 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.44
DANN	Benign	0.58
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3025694; hg19: chr16-3820667; COSMIC: COSV52117511; COSMIC: COSV52117511;