rs2239316

Variant names:

• chr16-3863994-A-G
• rs2239316
• NM_004380.3:c.86-12985T>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.86-12985T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 152,032 control chromosomes in the GnomAD database, including 8,744 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 0.33 (8744 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.343
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.86-12985T>C		intron_variant	Intron 1 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.86-12985T>C		intron_variant	Intron 1 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.86-12985T>C		intron_variant	Intron 1 of 29	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49512 AN: 151914 Hom.: 8726 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.313

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.326 AC: 49570 AN: 152032 Hom.: 8744 Cov.: 32 AF XY: 0.328 AC XY: 24407 AN XY: 74320

African (AFR) AF: 0.444 AC: 18408 AN: 41464

American (AMR) AF: 0.303 AC: 4625 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 804 AN: 3468

East Asian (EAS) AF: 0.344 AC: 1778 AN: 5172

South Asian (SAS) AF: 0.444 AC: 2139 AN: 4816

European-Finnish (FIN) AF: 0.289 AC: 3057 AN: 10574

Middle Eastern (MID) AF: 0.250 AC: 73 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17845 AN: 67950

Other (OTH) AF: 0.315 AC: 664 AN: 2110

Alfa AF: 0.281 Hom.: 26911

Bravo AF: 0.331

Asia WGS AF: 0.425 AC: 1476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.69
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2239316; hg19: chr16-3913995;