16-3761555-A-G

Position:

• chr16-3761555-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000262367.10(CREBBP):​c.3251-2583T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.419 in 517,196 control chromosomes in the GnomAD database, including 46,407 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 0.45 (15758 hom., cov: 30)
  • Exomes 𝑓: 0.40 (30649 hom.)
• Consequence: CREBBP ENST00000262367.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3251-2583T>C		intron_variant		ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3251-2583T>C		intron_variant		1	NM_004380.3	ENSP00000262367	P1
CREBBP	ENST00000382070.7	c.3137-2583T>C		intron_variant		1		ENSP00000371502
CREBBP	ENST00000570939.2	c.1856-2583T>C		intron_variant		5		ENSP00000461002

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68601 AN: 151658 Hom.: 15734 Cov.: 30

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.438

Gnomad OTH AF: 0.438

GnomAD3 exomes AF: 0.407 AC: 92698 AN: 227576 Hom.: 19331 AF XY: 0.405 AC XY: 50957 AN XY: 125862

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.336

Gnomad ASJ exome AF: 0.417

Gnomad EAS exome AF: 0.428

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.434

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.405 AC: 147814 AN: 365420 Hom.: 30649 Cov.: 0 AF XY: 0.399 AC XY: 83608 AN XY: 209602

Gnomad4 AFR exome AF: 0.552

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.324

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.435

Gnomad4 OTH exome AF: 0.419

GnomAD4 genome AF: 0.452 AC: 68677 AN: 151776 Hom.: 15758 Cov.: 30 AF XY: 0.447 AC XY: 33164 AN XY: 74166

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.438

Gnomad4 OTH AF: 0.438

Alfa AF: 0.431 Hom.: 27524

Bravo AF: 0.464

Asia WGS AF: 0.372 AC: 1293 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.2
DANN	Benign	0.43

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: rs886528; hg19: chr16-3811556; COSMIC: COSV52123678; COSMIC: COSV52123678;