16-3761595-C-T

Variant names:

• chr16-3761595-C-T
• rs11076786
• NM_004380.3:c.3251-2623G>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.3251-2623G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 517,814 control chromosomes in the GnomAD database, including 3,638 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 0.13 (1577 hom., cov: 31)
  • Exomes 𝑓: 0.098 (2061 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 14 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.3251-2623G>A		intron_variant	Intron 16 of 30	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.3251-2623G>A		intron_variant	Intron 16 of 30	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.3137-2623G>A		intron_variant	Intron 15 of 29	1		ENSP00000371502.3
CREBBP	ENST00000570939.2	c.1856-2623G>A		intron_variant	Intron 11 of 22	5		ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19847 AN: 151976 Hom.: 1571 Cov.: 31

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0811

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.0790

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0918

Gnomad OTH AF: 0.141

GnomAD2 exomes AF: 0.103 AC: 23486 AN: 227276 AF XY: 0.102

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.178

Gnomad FIN exome AF: 0.0844

Gnomad NFE exome AF: 0.0974

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0977 AC: 35749 AN: 365720 Hom.: 2061 Cov.: 0 AF XY: 0.0964 AC XY: 20225 AN XY: 209756

African (AFR) AF: 0.228 AC: 2375 AN: 10422

American (AMR) AF: 0.0530 AC: 1920 AN: 36210

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 1620 AN: 11702

East Asian (EAS) AF: 0.184 AC: 2411 AN: 13102

South Asian (SAS) AF: 0.0792 AC: 5276 AN: 66620

European-Finnish (FIN) AF: 0.0819 AC: 1377 AN: 16822

Middle Eastern (MID) AF: 0.143 AC: 406 AN: 2844

European-Non Finnish (NFE) AF: 0.0969 AC: 18548 AN: 191438

Other (OTH) AF: 0.110 AC: 1816 AN: 16560

GnomAD4 genome AF: 0.131 AC: 19881 AN: 152094 Hom.: 1577 Cov.: 31 AF XY: 0.129 AC XY: 9585 AN XY: 74338

African (AFR) AF: 0.226 AC: 9389 AN: 41466

American (AMR) AF: 0.0810 AC: 1238 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3466

East Asian (EAS) AF: 0.177 AC: 915 AN: 5156

South Asian (SAS) AF: 0.0795 AC: 382 AN: 4804

European-Finnish (FIN) AF: 0.0843 AC: 894 AN: 10602

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.0918 AC: 6243 AN: 67990

Other (OTH) AF: 0.144 AC: 305 AN: 2112

Alfa AF: 0.104 Hom.: 1841

Bravo AF: 0.138

Asia WGS AF: 0.120 AC: 417 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.16
DANN	Benign	0.49
PhyloP100		-1.1
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: rs11076786; hg19: chr16-3811596; COSMIC: COSV107273027; COSMIC: COSV107273027;