rs129986

Positions:

• chr16-3754240-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 4338 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3699-2434A>G		intron_variant		ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3699-2434A>G		intron_variant		1	NM_004380.3	ENSP00000262367	P1
CREBBP	ENST00000382070.7	c.3585-2434A>G		intron_variant		1		ENSP00000371502
CREBBP	ENST00000570939.2	c.2304-2404A>G		intron_variant		5		ENSP00000461002
CREBBP	ENST00000573517.6	c.5-2434A>G		intron_variant		5		ENSP00000460474

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

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.0317

Gnomad4 ASJ AF: 0.0282

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0299

Gnomad4 FIN AF: 0.0197

Gnomad4 NFE AF: 0.0285

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0265 Hom.: 4

Bravo AF: 0.0296

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.7
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs129986; hg19: chr16-3804241;