rs546554430

chr16-3729218-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004380.3(CREBBP):c.5829G>A(p.Pro1943=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,525,842 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -5.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 16-3729218-C-T is Benign according to our data. Variant chr16-3729218-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158389.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}. Variant chr16-3729218-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-5.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00112 (168/150216) while in subpopulation SAS AF= 0.00445 (21/4716). AF 95% confidence interval is 0.00298. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.5829G>A	p.Pro1943=	synonymous_variant	31/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.5829G>A	p.Pro1943=	synonymous_variant	31/31	1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.5715G>A	p.Pro1905=	synonymous_variant	30/30	1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 168 AN: 150106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00445

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000488

GnomAD3 exomes AF: 0.00143 AC: 187 AN: 130350 Hom.: 1 AF XY: 0.00183 AC XY: 130 AN XY: 71150

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00401

Gnomad NFE exome AF: 0.00178

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.00193 AC: 2653 AN: 1375626 Hom.: 6 Cov.: 35 AF XY: 0.00201 AC XY: 1366 AN XY: 678032

Gnomad4 AFR exome AF: 0.000255

Gnomad4 AMR exome AF: 0.0000282

Gnomad4 ASJ exome AF: 0.0000804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00341

Gnomad4 FIN exome AF: 0.00440

Gnomad4 NFE exome AF: 0.00201

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00112 AC: 168 AN: 150216 Hom.: 0 Cov.: 31 AF XY: 0.00112 AC XY: 82 AN XY: 73312

Gnomad4 AFR AF: 0.000172

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00445

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000483

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.000737

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CREBBP: BP4, BP7, BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 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

Jan 18, 2024

- -

CREBBP-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	5.8
Dann	Benign	0.70

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: rs546554430; hg19: chr16-3779219;