rs148781922

Variant names:

• chr16-3850335-C-A
• rs148781922
• NM_004380.3:c.760G>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3850335-C-A
• chr16-3850335-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004380.3(CREBBP):​c.760G>T​(p.Ala254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A254V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.649
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107180774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.760G>T	p.Ala254Ser	missense_variant	Exon 2 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.760G>T	p.Ala254Ser	missense_variant	Exon 2 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.760G>T	p.Ala254Ser	missense_variant	Exon 2 of 30	1		ENSP00000371502.3
CREBBP	ENST00000636895.1	n.-14G>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

CREBBP-related disorder Uncertain:1

Jan 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CREBBP c.760G>T variant is predicted to result in the amino acid substitution p.Ala254Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Rubinstein-Taybi syndrome Uncertain:1

Jul 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 254 of the CREBBP protein (p.Ala254Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CREBBP-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CREBBP protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.6
DANN	Benign	0.75
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.7	L;L
PhyloP100		0.65
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.24
Sift	Benign	0.079	T;T
Sift4G	Benign	0.65	T;T
Polyphen		0.63	P;.
Vest4		0.17
MutPred		0.15		Gain of glycosylation at A254 (P = 0.0064);Gain of glycosylation at A254 (P = 0.0064);
MVP		0.68
MPC		0.19
ClinPred		0.17	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.11
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148781922; hg19: chr16-3900336;