16-3793453-C-T

Variant names:

• chr16-3793453-C-T
• rs61759495
• NM_004380.3:c.1149G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_004380.3(CREBBP):​c.1149G>A​(p.Pro383Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,614,070 control chromosomes in the GnomAD database, including 12 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 0.0018 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -4.33
• Publications: 2 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=-0.64).
• BP6: Variant 16-3793453-C-T is Benign according to our data. Variant chr16-3793453-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95023.
• BP7: Synonymous conserved (PhyloP=-4.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00175 (267/152214) while in subpopulation AMR AF = 0.00504 (77/15284). AF 95% confidence interval is 0.00413. There are 2 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 267 AD gene.

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.1149G>A	p.Pro383Pro	synonymous	Exon 4 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.1149G>A	p.Pro383Pro	synonymous	Exon 4 of 30	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.1149G>A	p.Pro383Pro	synonymous	Exon 4 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.1149G>A	p.Pro383Pro	synonymous	Exon 4 of 30	ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152096 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00184 AC: 463 AN: 251486 AF XY: 0.00197

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00165 AC: 2407 AN: 1461856 Hom.: 10 Cov.: 32 AF XY: 0.00165 AC XY: 1197 AN XY: 727234

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 537 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86254

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53414

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.00137 AC: 1521 AN: 1111986

Other (OTH) AF: 0.00267 AC: 161 AN: 60396

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152214 Hom.: 2 Cov.: 31 AF XY: 0.00190 AC XY: 141 AN XY: 74402

African (AFR) AF: 0.000217 AC: 9 AN: 41536

American (AMR) AF: 0.00504 AC: 77 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00150 AC: 102 AN: 68014

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00205 Hom.: 1

Bravo AF: 0.00239

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CREBBP-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Rubinstein-Taybi syndrome (1)
-	1	-	Rubinstein-Taybi syndrome due to CREBBP mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.5
DANN	Benign	0.90
PhyloP100		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=82/18	polymorphism

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: rs61759495; hg19: chr16-3843454; COSMIC: COSV52113394; COSMIC: COSV52113394;