rs12599143

Variant names:

• chr16-3800415-G-A
• rs12599143
• NM_004380.3:c.976-6789C>T

Variant summary

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

The NM_004380.3(CREBBP):​c.976-6789C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 152,114 control chromosomes in the GnomAD database, including 697 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 0.082 (697 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.912
• Publications: 1 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.976-6789C>T		intron_variant	Intron 3 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.976-6789C>T		intron_variant	Intron 3 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.976-6789C>T		intron_variant	Intron 3 of 29	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12512 AN: 151996 Hom.: 695 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.0629

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.287

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.0823 AC: 12525 AN: 152114 Hom.: 697 Cov.: 32 AF XY: 0.0832 AC XY: 6183 AN XY: 74352

African (AFR) AF: 0.0349 AC: 1446 AN: 41490

American (AMR) AF: 0.0628 AC: 959 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 345 AN: 3472

East Asian (EAS) AF: 0.287 AC: 1486 AN: 5176

South Asian (SAS) AF: 0.103 AC: 496 AN: 4812

European-Finnish (FIN) AF: 0.0810 AC: 857 AN: 10578

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0971 AC: 6600 AN: 67996

Other (OTH) AF: 0.105 AC: 221 AN: 2108

Alfa AF: 0.0816 Hom.: 80

Bravo AF: 0.0803

Asia WGS AF: 0.156 AC: 541 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.3
DANN	Benign	0.64
PhyloP100		-0.91
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: rs12599143; hg19: chr16-3850416;