NM_004380.3:c.1651C>A

Variant names:

• chr16-3781229-G-T
• rs61753381
• NM_004380.3:c.1651C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004380.3(CREBBP):​c.1651C>A​(p.Leu551Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00973 in 1,613,964 control chromosomes in the GnomAD database, including 153 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 0.0076 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (140 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9 O:1
• Conservation: PhyloP100: 5.82
• Publications: 38 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007070422).
• BP6: Variant 16-3781229-G-T is Benign according to our data. Variant chr16-3781229-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95026.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00764 (1163/152270) while in subpopulation EAS AF = 0.0129 (67/5186). AF 95% confidence interval is 0.0104. There are 13 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1163 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.1651C>A	p.Leu551Ile	missense	Exon 7 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.1537C>A	p.Leu513Ile	missense	Exon 6 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.1651C>A	p.Leu551Ile	missense	Exon 7 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.1537C>A	p.Leu513Ile	missense	Exon 6 of 30	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.256C>A	p.Leu86Ile	missense	Exon 2 of 23	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152152 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.0103 AC: 2584 AN: 251442 AF XY: 0.0109

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.0592

Gnomad EAS exome AF: 0.0164

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00908

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.00995 AC: 14541 AN: 1461694 Hom.: 140 Cov.: 31 AF XY: 0.0102 AC XY: 7437 AN XY: 727160

African (AFR) AF: 0.00185 AC: 62 AN: 33478

American (AMR) AF: 0.00555 AC: 248 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 1522 AN: 26118

East Asian (EAS) AF: 0.0236 AC: 936 AN: 39692

South Asian (SAS) AF: 0.0113 AC: 974 AN: 86248

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53408

Middle Eastern (MID) AF: 0.0370 AC: 213 AN: 5762

European-Non Finnish (NFE) AF: 0.00868 AC: 9656 AN: 1111872

Other (OTH) AF: 0.0137 AC: 830 AN: 60394

GnomAD4 genome AF: 0.00764 AC: 1163 AN: 152270 Hom.: 13 Cov.: 32 AF XY: 0.00759 AC XY: 565 AN XY: 74442

African (AFR) AF: 0.00173 AC: 72 AN: 41550

American (AMR) AF: 0.00857 AC: 131 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0617 AC: 214 AN: 3468

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5186

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4828

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10610

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00844 AC: 574 AN: 68020

Other (OTH) AF: 0.0128 AC: 27 AN: 2114

Alfa AF: 0.0116 Hom.: 13

Bravo AF: 0.00774

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.0100 AC: 1214

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0121

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not specified (6)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (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
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0071	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.052	T
Sift4G	Benign	0.30	T
Polyphen		0.60	P
Vest4		0.23
MPC		1.3
ClinPred		0.017	T
GERP RS		5.5
PromoterAI		-0.0078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.19
Mutation Taster		=69/31	polymorphism (auto)

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: rs61753381; hg19: chr16-3831230; COSMIC: COSV52134580; COSMIC: COSV52134580;