rs130005

Variant names:

• chr16-3778347-A-G
• rs130005
• NM_004380.3:c.1942-165T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004380.3(CREBBP):​c.1942-165T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 152,268 control chromosomes in the GnomAD database, including 754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.082 (754 hom., cov: 32)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.287
• Publications: 13 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-3778347-A-G is Benign according to our data. Variant chr16-3778347-A-G is described in ClinVar as Benign. ClinVar VariationId is 1239359.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 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.1942-165T>C		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.1828-165T>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.1942-165T>C		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.1828-165T>C		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.547-165T>C		intron	N/A	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.0825 AC: 12552 AN: 152150 Hom.: 752 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.0825 AC: 12560 AN: 152268 Hom.: 754 Cov.: 32 AF XY: 0.0844 AC XY: 6284 AN XY: 74444

African (AFR) AF: 0.0187 AC: 776 AN: 41556

American (AMR) AF: 0.0648 AC: 992 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3472

East Asian (EAS) AF: 0.300 AC: 1554 AN: 5184

South Asian (SAS) AF: 0.108 AC: 520 AN: 4820

European-Finnish (FIN) AF: 0.102 AC: 1084 AN: 10598

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6937 AN: 68020

Other (OTH) AF: 0.110 AC: 232 AN: 2114

Alfa AF: 0.0975 Hom.: 2431

Bravo AF: 0.0786

Asia WGS AF: 0.158 AC: 548 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.7
DANN	Benign	0.64
PhyloP100		0.29
PromoterAI		-0.0091	Neutral
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: rs130005; hg19: chr16-3828348;