16-3729247-A-G

Variant names:

• chr16-3729247-A-G
• rs587783504
• NM_004380.3:c.5800T>C

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.5800T>C​(p.Ser1934Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,526,834 control chromosomes in the GnomAD database, including 1 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 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: CREBBP NM_004380.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 5.09
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056996673).
• BP6: Variant 16-3729247-A-G is Benign according to our data. Variant chr16-3729247-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158387.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000293 (44/150386) while in subpopulation NFE AF = 0.000548 (37/67498). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 44 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.5800T>C	p.Ser1934Pro	missense	Exon 31 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.5686T>C	p.Ser1896Pro	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.5800T>C	p.Ser1934Pro	missense	Exon 31 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.5686T>C	p.Ser1896Pro	missense	Exon 30 of 30	ENSP00000371502.3	Q92793-2

Frequencies

GnomAD3 genomes AF: 0.000299 AC: 45 AN: 150270 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

Gnomad ASJ AF: 0.000867

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000548

Gnomad OTH AF: 0.000484

GnomAD2 exomes AF: 0.000350 AC: 46 AN: 131462 AF XY: 0.000323

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000715

Gnomad OTH exome AF: 0.000249

GnomAD4 exome AF: 0.000384 AC: 528 AN: 1376448 Hom.: 1 Cov.: 35 AF XY: 0.000373 AC XY: 253 AN XY: 678226

African (AFR) AF: 0.0000637 AC: 2 AN: 31406

American (AMR) AF: 0.000169 AC: 6 AN: 35522

Ashkenazi Jewish (ASJ) AF: 0.00141 AC: 35 AN: 24798

East Asian (EAS) AF: 0.00 AC: 0 AN: 35618

South Asian (SAS) AF: 0.000102 AC: 8 AN: 78612

European-Finnish (FIN) AF: 0.0000583 AC: 2 AN: 34292

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4152

European-Non Finnish (NFE) AF: 0.000418 AC: 449 AN: 1074618

Other (OTH) AF: 0.000348 AC: 20 AN: 57430

GnomAD4 genome AF: 0.000293 AC: 44 AN: 150386 Hom.: 0 Cov.: 32 AF XY: 0.000300 AC XY: 22 AN XY: 73396

African (AFR) AF: 0.0000491 AC: 2 AN: 40758

American (AMR) AF: 0.0000659 AC: 1 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.000867 AC: 3 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5056

South Asian (SAS) AF: 0.00 AC: 0 AN: 4762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10384

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

European-Non Finnish (NFE) AF: 0.000548 AC: 37 AN: 67498

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000941 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.0000709 AC: 6

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	CREBBP-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)
-	1	-	Rubinstein-Taybi syndrome due to CREBBP mutations (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.14
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.95	L
PhyloP100		5.1
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.48
Sift	Benign	0.068	T
Sift4G	Benign	0.24	T
Polyphen		0.014	B
Vest4		0.10
MVP		0.99
MPC		1.6
ClinPred		0.056	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.20
Mutation Taster		=69/31	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: rs587783504; hg19: chr16-3779248; COSMIC: COSV105864154; COSMIC: COSV105864154;