rs129986

Variant names:

• chr16-3754240-T-C
• rs129986
• NM_004380.3:c.3699-2434A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004380.3(CREBBP):​c.3699-2434A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 152,296 control chromosomes in the GnomAD database, including 59 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 0.028 (59 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340
• Publications: 2 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=-0.95).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0285 (4338/152296) while in subpopulation AMR AF = 0.0317 (485/15294). AF 95% confidence interval is 0.0299. There are 59 homozygotes in GnomAd4. There are 2080 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4338 AD gene.

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.3699-2434A>G		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.3585-2434A>G		intron	N/A	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.3699-2434A>G		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.3585-2434A>G		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.2304-2404A>G		intron	N/A	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4342 AN: 152178 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0318

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0426

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

GnomAD4 genome AF: 0.0285 AC: 4338 AN: 152296 Hom.: 59 Cov.: 32 AF XY: 0.0279 AC XY: 2080 AN XY: 74462

African (AFR) AF: 0.0313 AC: 1302 AN: 41542

American (AMR) AF: 0.0317 AC: 485 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.0299 AC: 144 AN: 4824

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0285 AC: 1942 AN: 68026

Other (OTH) AF: 0.0421 AC: 89 AN: 2112

Alfa AF: 0.0282 Hom.: 83

Bravo AF: 0.0296

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.7
DANN	Benign	0.58
PhyloP100		0.034
Mutation Taster		=100/0	polymorphism

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: rs129986; hg19: chr16-3804241;