16-3850335-C-T

Variant names:

• chr16-3850335-C-T
• rs148781922
• NM_004380.3:c.760G>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.760G>A​(p.Ala254Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,614,242 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Likely benign (★★). 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: 𝑓 0.00054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.649
• Publications: 14 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=0.0073812604).
• BP6: Variant 16-3850335-C-T is Benign according to our data. Variant chr16-3850335-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000538 (82/152354) while in subpopulation EAS AF = 0.00829 (43/5186). AF 95% confidence interval is 0.00633. There are 0 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 82 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.760G>A	p.Ala254Thr	missense	Exon 2 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.760G>A	p.Ala254Thr	missense	Exon 2 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.760G>A	p.Ala254Thr	missense	Exon 2 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.760G>A	p.Ala254Thr	missense	Exon 2 of 30	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000636895.1	TSL:5	n.-14G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152236 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00808

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000697 AC: 175 AN: 250994 AF XY: 0.000611

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00799

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000254 AC: 372 AN: 1461888 Hom.: 2 Cov.: 31 AF XY: 0.000227 AC XY: 165 AN XY: 727246

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00494 AC: 196 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112012

Other (OTH) AF: 0.00210 AC: 127 AN: 60396

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152354 Hom.: 0 Cov.: 30 AF XY: 0.000604 AC XY: 45 AN XY: 74502

African (AFR) AF: 0.000673 AC: 28 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00829 AC: 43 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68032

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

Alfa AF: 0.000646 Hom.: 1

Bravo AF: 0.000627

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CREBBP-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (2)
-	-	1	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.4
DANN	Benign	0.71
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.65
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.22
Sift	Benign	0.51	T
Sift4G	Benign	0.77	T
Polyphen		0.61	P
Vest4		0.13
MVP		0.66
MPC		0.18
ClinPred		0.0069	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.013
gMVP		0.13
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV52129042;