16-3867530-A-G

Variant names:

• chr16-3867530-A-G
• rs2526690
• NM_004380.3:c.85+12302T>C

Variant summary

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

The NM_004380.3(CREBBP):​c.85+12302T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.872 in 152,058 control chromosomes in the GnomAD database, including 59,711 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 0.87 (59711 hom., cov: 30)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.495
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

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.85+12302T>C		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.85+12302T>C		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.85+12302T>C		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.85+12302T>C		intron	N/A	ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132548 AN: 151940 Hom.: 59696 Cov.: 30

Gnomad AFR AF: 0.630

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.933

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.794

Gnomad SAS AF: 0.878

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.987

Gnomad OTH AF: 0.884

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

GnomAD4 genome AF: 0.872 AC: 132597 AN: 152058 Hom.: 59711 Cov.: 30 AF XY: 0.874 AC XY: 65024 AN XY: 74372

African (AFR) AF: 0.629 AC: 26039 AN: 41380

American (AMR) AF: 0.934 AC: 14266 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3202 AN: 3472

East Asian (EAS) AF: 0.793 AC: 4106 AN: 5176

South Asian (SAS) AF: 0.879 AC: 4229 AN: 4812

European-Finnish (FIN) AF: 0.997 AC: 10560 AN: 10596

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.987 AC: 67167 AN: 68026

Other (OTH) AF: 0.886 AC: 1867 AN: 2108

Alfa AF: 0.922 Hom.: 8195

Bravo AF: 0.855

Asia WGS AF: 0.815 AC: 2835 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.66
PhyloP100		0.49
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: rs2526690; hg19: chr16-3917531;