rs130018

Positions:

• chr16-3781186-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004380.3(CREBBP):​c.1676+18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,603,678 control chromosomes in the GnomAD database, including 2,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (1152 hom., cov: 32)
  • Exomes 𝑓: 0.017 (1208 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.497

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-3781186-T-A is Benign according to our data. Variant chr16-3781186-T-A is described in ClinVar as [Benign]. Clinvar id is 95028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.1676+18A>T		intron_variant		ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.1676+18A>T		intron_variant		1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.1562+18A>T		intron_variant		1
CREBBP	ENST00000570939.2	c.281+18A>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11386 AN: 152084 Hom.: 1144 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0288 AC: 7232 AN: 251126 Hom.: 534 AF XY: 0.0244 AC XY: 3317 AN XY: 135714

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.0164

Gnomad SAS exome AF: 0.0133

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00988

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0173 AC: 25088 AN: 1451476 Hom.: 1208 Cov.: 29 AF XY: 0.0166 AC XY: 11981 AN XY: 722788

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.0222

Gnomad4 ASJ exome AF: 0.0627

Gnomad4 EAS exome AF: 0.0236

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00920

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0751 AC: 11437 AN: 152202 Hom.: 1152 Cov.: 32 AF XY: 0.0713 AC XY: 5307 AN XY: 74422

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0665

Gnomad4 EAS AF: 0.0133

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00944

Gnomad4 OTH AF: 0.0715

Alfa AF: 0.0445 Hom.: 96

Bravo AF: 0.0870

Asia WGS AF: 0.0370 AC: 129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs130018; hg19: chr16-3831187;