16-3788297-C-T

Variant names:

• chr16-3788297-C-T
• rs8046065
• NM_004380.3:c.1330+3684G>A

Variant summary

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

The NM_004380.3(CREBBP):​c.1330+3684G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,202 control chromosomes in the GnomAD database, including 2,863 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 0.18 (2863 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.633
• Publications: 17 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.1330+3684G>A		intron_variant	Intron 5 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.1330+3684G>A		intron_variant	Intron 5 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.1216+5089G>A		intron_variant	Intron 4 of 29	1		ENSP00000371502.3
CREBBP	ENST00000635753.1	n.63+2896G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27358 AN: 152084 Hom.: 2862 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.0749

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.180 AC: 27382 AN: 152202 Hom.: 2863 Cov.: 32 AF XY: 0.184 AC XY: 13666 AN XY: 74414

African (AFR) AF: 0.270 AC: 11221 AN: 41514

American (AMR) AF: 0.238 AC: 3643 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 560 AN: 3472

East Asian (EAS) AF: 0.0752 AC: 390 AN: 5184

South Asian (SAS) AF: 0.211 AC: 1018 AN: 4822

European-Finnish (FIN) AF: 0.154 AC: 1630 AN: 10594

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8337 AN: 68014

Other (OTH) AF: 0.188 AC: 397 AN: 2112

Alfa AF: 0.141 Hom.: 4029

Bravo AF: 0.188

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.70
DANN	Benign	0.50
PhyloP100		-0.63
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: rs8046065; hg19: chr16-3838298;