rs181646656

Variant names:

• chr16-3729059-G-A
• rs181646656
• NM_004380.3:c.5988C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-3729059-G-A
• chr16-3729059-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004380.3(CREBBP):​c.5988C>T​(p.Ala1996Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,584,672 control chromosomes in the GnomAD database, including 257 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (22 hom., cov: 32)
  • Exomes 𝑓: 0.011 (235 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.14
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-3729059-G-A is Benign according to our data. Variant chr16-3729059-G-A is described in ClinVar as Benign. ClinVar VariationId is 95058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00784 (1194/152214) while in subpopulation SAS AF = 0.0537 (259/4824). AF 95% confidence interval is 0.0483. There are 22 homozygotes in GnomAd4. There are 627 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1194 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.5988C>T	p.Ala1996Ala	synonymous	Exon 31 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.5874C>T	p.Ala1958Ala	synonymous	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.5988C>T	p.Ala1996Ala	synonymous	Exon 31 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.5874C>T	p.Ala1958Ala	synonymous	Exon 30 of 30	ENSP00000371502.3	Q92793-2

Frequencies

GnomAD3 genomes AF: 0.00785 AC: 1194 AN: 152096 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00825

Gnomad ASJ AF: 0.0475

Gnomad EAS AF: 0.0103

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00709

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0150 AC: 3017 AN: 200776 AF XY: 0.0175

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.0464

Gnomad EAS exome AF: 0.0145

Gnomad FIN exome AF: 0.00150

Gnomad NFE exome AF: 0.00828

Gnomad OTH exome AF: 0.0140

GnomAD4 exome AF: 0.0113 AC: 16217 AN: 1432458 Hom.: 235 Cov.: 33 AF XY: 0.0127 AC XY: 9011 AN XY: 711678

African (AFR) AF: 0.00188 AC: 62 AN: 33016

American (AMR) AF: 0.00535 AC: 225 AN: 42058

Ashkenazi Jewish (ASJ) AF: 0.0463 AC: 1192 AN: 25740

East Asian (EAS) AF: 0.0203 AC: 780 AN: 38478

South Asian (SAS) AF: 0.0497 AC: 4164 AN: 83800

European-Finnish (FIN) AF: 0.00194 AC: 80 AN: 41144

Middle Eastern (MID) AF: 0.0308 AC: 177 AN: 5742

European-Non Finnish (NFE) AF: 0.00788 AC: 8688 AN: 1103036

Other (OTH) AF: 0.0143 AC: 849 AN: 59444

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152214 Hom.: 22 Cov.: 32 AF XY: 0.00843 AC XY: 627 AN XY: 74416

African (AFR) AF: 0.00161 AC: 67 AN: 41548

American (AMR) AF: 0.00824 AC: 126 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 165 AN: 3472

East Asian (EAS) AF: 0.0101 AC: 52 AN: 5156

South Asian (SAS) AF: 0.0537 AC: 259 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00709 AC: 482 AN: 67988

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.0119 Hom.: 5

Bravo AF: 0.00709

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Rubinstein-Taybi syndrome (1)
-	-	1	Rubinstein-Taybi syndrome due to CREBBP mutations;C5193034:Menke-Hennekam syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.9
DANN	Benign	0.72
PhyloP100		1.1
Mutation Taster		=97/3	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: rs181646656; hg19: chr16-3779060; COSMIC: COSV107273010; COSMIC: COSV107273010;