NM_004380.3:c.6685G>A

Variant names:

• chr16-3728362-C-T
• rs139688311
• NM_004380.3:c.6685G>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.6685G>A​(p.Gly2229Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,607,362 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. G2229D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.09
• Publications: 7 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=0.004820019).
• BP6: Variant 16-3728362-C-T is Benign according to our data. Variant chr16-3728362-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00474 (720/152050) while in subpopulation AFR AF = 0.0149 (617/41482). AF 95% confidence interval is 0.0139. There are 8 homozygotes in GnomAd4. There are 343 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 720 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.6685G>A	p.Gly2229Ser	missense	Exon 31 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.6571G>A	p.Gly2191Ser	missense	Exon 30 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.6685G>A	p.Gly2229Ser	missense	Exon 31 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.6571G>A	p.Gly2191Ser	missense	Exon 30 of 30	ENSP00000371502.3	Q92793-2

Frequencies

GnomAD3 genomes AF: 0.00474 AC: 720 AN: 151934 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00195 AC: 446 AN: 228750 AF XY: 0.00167

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000703

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00322

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.00158

GnomAD4 exome AF: 0.00119 AC: 1725 AN: 1455312 Hom.: 9 Cov.: 33 AF XY: 0.00115 AC XY: 832 AN XY: 723684

African (AFR) AF: 0.0137 AC: 455 AN: 33330

American (AMR) AF: 0.000599 AC: 26 AN: 43386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.000373 AC: 32 AN: 85728

European-Finnish (FIN) AF: 0.00258 AC: 135 AN: 52316

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5604

European-Non Finnish (NFE) AF: 0.000880 AC: 977 AN: 1109612

Other (OTH) AF: 0.00165 AC: 99 AN: 60030

GnomAD4 genome AF: 0.00474 AC: 720 AN: 152050 Hom.: 8 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74336

African (AFR) AF: 0.0149 AC: 617 AN: 41482

American (AMR) AF: 0.00118 AC: 18 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00330 AC: 35 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67906

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00136 Hom.: 1

Bravo AF: 0.00541

ESP6500AA AF: 0.0155 AC: 68

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00237 AC: 287

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.29
DANN	Benign	0.67
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.17
Sift	Benign	0.49	T
Sift4G	Benign	0.15	T
Polyphen		0.0030	B
Vest4		0.064
MVP		0.59
MPC		0.38
ClinPred		0.0014	T
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.20
Mutation Taster		=98/2	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: rs139688311; hg19: chr16-3778363; COSMIC: COSV106088794; COSMIC: COSV106088794;