NM_004380.3:c.2941G>A

Variant names:

• chr16-3769293-C-T
• rs61753380
• NM_004380.3:c.2941G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004380.3(CREBBP):​c.2941G>A​(p.Ala981Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,118 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A981V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (18 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:2
• Conservation: PhyloP100: 1.16
• Publications: 20 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: Illumina, ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058826804).
• BP6: Variant 16-3769293-C-T is Benign according to our data. Variant chr16-3769293-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.003 (457/152240) while in subpopulation NFE AF = 0.0056 (381/68016). AF 95% confidence interval is 0.00514. There are 0 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 457 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.2941G>A	p.Ala981Thr	missense	Exon 15 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.2827G>A	p.Ala943Thr	missense	Exon 14 of 30	NP_001073315.1	Q92793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.2941G>A	p.Ala981Thr	missense	Exon 15 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.2827G>A	p.Ala943Thr	missense	Exon 14 of 30	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000570939.2	TSL:5	c.1546G>A	p.Ala516Thr	missense	Exon 10 of 23	ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00346 AC: 870 AN: 251342 AF XY: 0.00350

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00594

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00425 AC: 6216 AN: 1461878 Hom.: 18 Cov.: 32 AF XY: 0.00426 AC XY: 3098 AN XY: 727242

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00758 AC: 198 AN: 26134

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

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.000936 AC: 50 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.00505 AC: 5614 AN: 1112006

Other (OTH) AF: 0.00382 AC: 231 AN: 60396

GnomAD4 genome AF: 0.00300 AC: 457 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74440

African (AFR) AF: 0.000650 AC: 27 AN: 41540

American (AMR) AF: 0.000981 AC: 15 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00560 AC: 381 AN: 68016

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00448 Hom.: 1

Bravo AF: 0.00287

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00387 AC: 470

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)
-	-	-	Rubinstein-Taybi syndrome due to CREBBP mutations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.65
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.72	N
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.41
Sift	Benign	0.76	T
Sift4G	Benign	0.67	T
Polyphen		0.0020	B
Vest4		0.16
MVP		0.91
MPC		0.086
ClinPred		0.0085	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.24
Mutation Taster		=97/3	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: rs61753380; hg19: chr16-3819294; COSMIC: COSV99273423;