16-3769260-C-T

Variant names:

• chr16-3769260-C-T
• rs61731383
• NM_004380.3:c.2974G>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.2974G>A​(p.Val992Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,152 control chromosomes in the GnomAD database, including 77 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (47 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.67
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021652877).
• BP6: Variant 16-3769260-C-T is Benign according to our data. Variant chr16-3769260-C-T is described in ClinVar as Benign. ClinVar VariationId is 95040.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 = 0.0133 (2018/152260) while in subpopulation AFR AF = 0.0461 (1914/41524). AF 95% confidence interval is 0.0444. There are 47 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2018 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.2974G>A	p.Val992Ile	missense	Exon 15 of 31	NP_004371.2
	CREBBP	NM_001079846.1		c.2860G>A	p.Val954Ile	missense	Exon 14 of 30	NP_001073315.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.2974G>A	p.Val992Ile	missense	Exon 15 of 31	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.2860G>A	p.Val954Ile	missense	Exon 14 of 30	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.1579G>A	p.Val527Ile	missense	Exon 10 of 23	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2012 AN: 152142 Hom.: 46 Cov.: 31

Gnomad AFR AF: 0.0461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00346 AC: 869 AN: 251468 AF XY: 0.00238

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00130 AC: 1898 AN: 1461892 Hom.: 30 Cov.: 32 AF XY: 0.00109 AC XY: 795 AN XY: 727246

African (AFR) AF: 0.0466 AC: 1559 AN: 33480

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

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

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1112012

Other (OTH) AF: 0.00252 AC: 152 AN: 60396

GnomAD4 genome AF: 0.0133 AC: 2018 AN: 152260 Hom.: 47 Cov.: 31 AF XY: 0.0120 AC XY: 895 AN XY: 74452

African (AFR) AF: 0.0461 AC: 1914 AN: 41524

American (AMR) AF: 0.00477 AC: 73 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00328 Hom.: 24

Bravo AF: 0.0155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0453 AC: 199

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00446 AC: 542

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (4)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.14
Sift	Benign	0.39	T
Sift4G	Benign	0.45	T
Polyphen		0.0	B
Vest4		0.082
MVP		0.54
MPC		0.073
ClinPred		0.0026	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.046
Mutation Taster		=99/1	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: rs61731383; hg19: chr16-3819261; COSMIC: COSV108776187; COSMIC: COSV108776187;