rs130003

Variant names:

• chr16-3778171-A-G
• rs130003
• NM_004380.3:c.1953T>C

Your query was ambiguous. Multiple possible variants found:

• chr16-3778171-A-G
• chr16-3778171-A-C
• chr16-3778171-A-T

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.1953T>C​(p.Tyr651Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,604,394 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (28 hom., cov: 32)
  • Exomes 𝑓: 0.020 (384 hom.)
• Consequence: CREBBP NM_004380.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.11
• Publications: 8 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 (BayesDel_noAF=-0.5).
• BP6: Variant 16-3778171-A-G is Benign according to our data. Variant chr16-3778171-A-G is described in ClinVar as Benign. ClinVar VariationId is 158342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0149 (2267/152330) while in subpopulation NFE AF = 0.0233 (1586/68028). AF 95% confidence interval is 0.0224. There are 28 homozygotes in GnomAd4. There are 1063 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2267 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.1953T>C	p.Tyr651Tyr	synonymous	Exon 10 of 31	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.1839T>C	p.Tyr613Tyr	synonymous	Exon 9 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.1953T>C	p.Tyr651Tyr	synonymous	Exon 10 of 31	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.1839T>C	p.Tyr613Tyr	synonymous	Exon 9 of 30	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000570939.2	TSL:5	c.558T>C	p.Tyr186Tyr	synonymous	Exon 5 of 23	ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2268 AN: 152212 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.00478

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0149 AC: 3732 AN: 250538 AF XY: 0.0156

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0199 AC: 28880 AN: 1452064 Hom.: 384 Cov.: 30 AF XY: 0.0196 AC XY: 14175 AN XY: 723044

African (AFR) AF: 0.00370 AC: 123 AN: 33206

American (AMR) AF: 0.0133 AC: 596 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 533 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00526 AC: 453 AN: 86048

European-Finnish (FIN) AF: 0.00565 AC: 302 AN: 53410

Middle Eastern (MID) AF: 0.0258 AC: 148 AN: 5726

European-Non Finnish (NFE) AF: 0.0231 AC: 25522 AN: 1103166

Other (OTH) AF: 0.0200 AC: 1203 AN: 60062

GnomAD4 genome AF: 0.0149 AC: 2267 AN: 152330 Hom.: 28 Cov.: 32 AF XY: 0.0143 AC XY: 1063 AN XY: 74502

African (AFR) AF: 0.00476 AC: 198 AN: 41566

American (AMR) AF: 0.0187 AC: 287 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4824

European-Finnish (FIN) AF: 0.00395 AC: 42 AN: 10620

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1586 AN: 68028

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0221 Hom.: 155

Bravo AF: 0.0160

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0266

EpiControl AF: 0.0245

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.9
DANN	Benign	0.66
PhyloP100		2.1
PromoterAI		0.0061	Neutral
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: rs130003; hg19: chr16-3828172;