16-3729210-G-C

Variant names:

• chr16-3729210-G-C
• rs765600316
• NM_004380.3:c.5837C>G

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.5837C>G​(p.Pro1946Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000218 in 1,374,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1946A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.82
• 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: 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=0.18604735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.5837C>G	p.Pro1946Arg	missense_variant	Exon 31 of 31	ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.5837C>G	p.Pro1946Arg	missense_variant	Exon 31 of 31	1	NM_004380.3	ENSP00000262367.5
CREBBP	ENST00000382070.7	c.5723C>G	p.Pro1908Arg	missense_variant	Exon 30 of 30	1		ENSP00000371502.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151840 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000218 AC: 3 AN: 1374896 Hom.: 0 Cov.: 38 AF XY: 0.00000147 AC XY: 1 AN XY: 678020

African (AFR) AF: 0.00 AC: 0 AN: 31376

American (AMR) AF: 0.00 AC: 0 AN: 35494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24846

East Asian (EAS) AF: 0.0000281 AC: 1 AN: 35646

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 9.31e-7 AC: 1 AN: 1073610

Other (OTH) AF: 0.00 AC: 0 AN: 57398

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000198 AC: 3 AN: 151840 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74144

African (AFR) AF: 0.0000242 AC: 1 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67912

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Benign	0.75
DEOGEN2	Uncertain	0.60	D;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.22
Sift	Benign	0.043	D;D
Sift4G	Benign	0.37	T;T
Polyphen		0.0050	B;.
Vest4		0.43
MutPred		0.30		Loss of glycosylation at P1946 (P = 0.0025);.;
MVP		0.82
MPC		1.4
ClinPred		0.37	T
GERP RS		4.2
Varity_R		0.11
gMVP		0.15
Mutation Taster		=94/6	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: rs765600316; hg19: chr16-3779211;