NM_004380.3:c.3251-2583T>C

Variant names:

• chr16-3761555-A-G
• rs886528
• NM_004380.3:c.3251-2583T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004380.3(CREBBP):​c.3251-2583T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 517,196 control chromosomes in the GnomAD database, including 46,407 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (15758 hom., cov: 30)
  • Exomes 𝑓: 0.40 (30649 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 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.3251-2583T>C		intron	N/A	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.3137-2583T>C		intron	N/A	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.3251-2583T>C		intron	N/A	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.3137-2583T>C		intron	N/A	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000570939.2	TSL:5	c.1856-2583T>C		intron	N/A	ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68601 AN: 151658 Hom.: 15734 Cov.: 30

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.438

GnomAD2 exomes AF: 0.407 AC: 92698 AN: 227576 AF XY: 0.405

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.405 AC: 147814 AN: 365420 Hom.: 30649 Cov.: 0 AF XY: 0.399 AC XY: 83608 AN XY: 209602

African (AFR) AF: 0.552 AC: 5758 AN: 10434

American (AMR) AF: 0.338 AC: 12197 AN: 36130

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 4905 AN: 11702

East Asian (EAS) AF: 0.435 AC: 5666 AN: 13040

South Asian (SAS) AF: 0.324 AC: 21576 AN: 66602

European-Finnish (FIN) AF: 0.383 AC: 6450 AN: 16858

Middle Eastern (MID) AF: 0.391 AC: 1114 AN: 2852

European-Non Finnish (NFE) AF: 0.435 AC: 83205 AN: 191250

Other (OTH) AF: 0.419 AC: 6943 AN: 16552

GnomAD4 genome AF: 0.452 AC: 68677 AN: 151776 Hom.: 15758 Cov.: 30 AF XY: 0.447 AC XY: 33164 AN XY: 74166

African (AFR) AF: 0.542 AC: 22419 AN: 41390

American (AMR) AF: 0.385 AC: 5869 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.411 AC: 1423 AN: 3466

East Asian (EAS) AF: 0.422 AC: 2164 AN: 5130

South Asian (SAS) AF: 0.324 AC: 1542 AN: 4766

European-Finnish (FIN) AF: 0.385 AC: 4070 AN: 10562

Middle Eastern (MID) AF: 0.342 AC: 100 AN: 292

European-Non Finnish (NFE) AF: 0.438 AC: 29745 AN: 67888

Other (OTH) AF: 0.438 AC: 925 AN: 2112

Alfa AF: 0.439 Hom.: 44894

Bravo AF: 0.464

Asia WGS AF: 0.372 AC: 1293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.2
DANN	Benign	0.43
PhyloP100		-0.19
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: rs886528; hg19: chr16-3811556; COSMIC: COSV52123678; COSMIC: COSV52123678;