16-3778171-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):c.1953T>C(p.Tyr651=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,604,394 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 32)
  • Exomes 𝑓: 0.020 (384 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.11

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=-0.5).
• BP6: Variant 16-3778171-A-G is Benign according to our data. Variant chr16-3778171-A-G is described in ClinVar as [Benign]. Clinvar id is 158342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-3778171-A-G is described in Lovd as [Likely_benign]. Variant chr16-3778171-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0149 (2267/152330) while in subpopulation NFE AF= 0.0233 (1586/68028). AF 95% confidence interval is 0.0224. There are 28 homozygotes in gnomad4. There are 1063 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2268 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.1953T>C	p.Tyr651=	synonymous_variant	10/31	ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.1953T>C	p.Tyr651=	synonymous_variant	10/31	1	NM_004380.3	P1

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2268 AN: 152212 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0149 AC: 3732 AN: 250538 Hom.: 55 AF XY: 0.0156 AC XY: 2114 AN XY: 135702

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00510

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0199 AC: 28880 AN: 1452064 Hom.: 384 Cov.: 30 AF XY: 0.0196 AC XY: 14175 AN XY: 723044

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00526

Gnomad4 FIN exome AF: 0.00565

Gnomad4 NFE exome AF: 0.0231

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0149 AC: 2267 AN: 152330 Hom.: 28 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74502

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.0187

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0232 Hom.: 92

Bravo AF: 0.0160

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0245

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	Eurofins Ntd Llc (ga)	Dec 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2013	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

This alteration is classified as 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.9
Dann	Benign	0.66

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: rs130003; hg19: chr16-3828172;