rs142528559

chr16-3769261-G-Achr16-3769261-G-Cchr16-3769261-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004380.3(CREBBP):c.2973C>T(p.Asp991=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,614,158 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-3769261-G-A is Benign according to our data. Variant chr16-3769261-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3769261-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00223 (340/152264) while in subpopulation NFE AF= 0.0037 (252/68020). AF 95% confidence interval is 0.00333. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.2973C>T	p.Asp991=	synonymous_variant	15/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.2973C>T	p.Asp991=	synonymous_variant	15/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.2859C>T	p.Asp953=	synonymous_variant	14/30	1
CREBBP	ENST00000570939.2	c.1578C>T	p.Asp526=	synonymous_variant	10/23	5
CREBBP	ENST00000573672.1	n.227C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152146 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00370

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00223 AC: 562 AN: 251466 Hom.: 1 AF XY: 0.00221 AC XY: 301 AN XY: 135916

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00359

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00251 AC: 3676 AN: 1461894 Hom.: 8 Cov.: 32 AF XY: 0.00258 AC XY: 1877 AN XY: 727248

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152264 Hom.: 1 Cov.: 31 AF XY: 0.00206 AC XY: 153 AN XY: 74444

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00370

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00328 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CREBBP: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	- -

Rubinstein-Taybi syndrome due to CREBBP mutations;C5193034:Menke-Hennekam syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2016

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.12
Dann	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs142528559; hg19: chr16-3819262;