chr16-3725168-G-A

Variant names:

• chr16-3725168-G-A
• rs9392
• NM_004380.3:c.*2550C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_004380.3(CREBBP):​c.*2550C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 233,296 control chromosomes in the GnomAD database, including 6,831 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 0.22 (3894 hom., cov: 33)
  • Exomes 𝑓: 0.25 (2937 hom.)
• Consequence: CREBBP NM_004380.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 20 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: 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)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.*2550C>T		3_prime_UTR	Exon 31 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.*2550C>T		3_prime_UTR	Exon 30 of 30	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.*2550C>T		3_prime_UTR	Exon 31 of 31	ENSP00000262367.5

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33458 AN: 152038 Hom.: 3894 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.252 AC: 20433 AN: 81140 Hom.: 2937 Cov.: 0 AF XY: 0.255 AC XY: 9527 AN XY: 37352

African (AFR) AF: 0.168 AC: 651 AN: 3878

American (AMR) AF: 0.153 AC: 381 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1764 AN: 5110

East Asian (EAS) AF: 0.435 AC: 4932 AN: 11350

South Asian (SAS) AF: 0.286 AC: 200 AN: 700

European-Finnish (FIN) AF: 0.257 AC: 122 AN: 474

Middle Eastern (MID) AF: 0.224 AC: 110 AN: 490

European-Non Finnish (NFE) AF: 0.216 AC: 10761 AN: 49894

Other (OTH) AF: 0.224 AC: 1512 AN: 6750

GnomAD4 genome AF: 0.220 AC: 33465 AN: 152156 Hom.: 3894 Cov.: 33 AF XY: 0.222 AC XY: 16523 AN XY: 74392

African (AFR) AF: 0.171 AC: 7099 AN: 41516

American (AMR) AF: 0.169 AC: 2584 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1115 AN: 3472

East Asian (EAS) AF: 0.426 AC: 2204 AN: 5168

South Asian (SAS) AF: 0.285 AC: 1372 AN: 4822

European-Finnish (FIN) AF: 0.264 AC: 2787 AN: 10574

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15494 AN: 68004

Other (OTH) AF: 0.220 AC: 464 AN: 2110

Alfa AF: 0.227 Hom.: 7083

Bravo AF: 0.210

Asia WGS AF: 0.305 AC: 1061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		1.8
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: rs9392; hg19: chr16-3775169;