rs130002

Variant names:

• chr16-3777930-T-C
• rs130002
• NM_004380.3:c.2113+81A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004380.3(CREBBP):​c.2113+81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,501,598 control chromosomes in the GnomAD database, including 2,152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (302 hom., cov: 32)
  • Exomes 𝑓: 0.021 (1850 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• 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 (BayesDel_noAF=-0.88).
• BP6: Variant 16-3777930-T-C is Benign according to our data. Variant chr16-3777930-T-C is described in ClinVar as Benign. ClinVar VariationId is 1249895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.2113+81A>G		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.1999+81A>G		intron	N/A	NP_001073315.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	ENST00000262367.10	TSL:1 MANE Select	c.2113+81A>G		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.1999+81A>G		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000570939.2	TSL:5	c.718+81A>G		intron	N/A	ENSP00000461002.2

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5941 AN: 152170 Hom.: 299 Cov.: 32

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00417

Gnomad OTH AF: 0.0306

GnomAD4 exome AF: 0.0208 AC: 28065 AN: 1349310 Hom.: 1850 Cov.: 21 AF XY: 0.0243 AC XY: 16472 AN XY: 677360

African (AFR) AF: 0.0843 AC: 2614 AN: 30996

American (AMR) AF: 0.0141 AC: 620 AN: 44100

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 537 AN: 25300

East Asian (EAS) AF: 0.177 AC: 6919 AN: 39130

South Asian (SAS) AF: 0.142 AC: 11757 AN: 82946

European-Finnish (FIN) AF: 0.00985 AC: 524 AN: 53180

Middle Eastern (MID) AF: 0.0344 AC: 190 AN: 5530

European-Non Finnish (NFE) AF: 0.00301 AC: 3045 AN: 1011512

Other (OTH) AF: 0.0328 AC: 1859 AN: 56616

GnomAD4 genome AF: 0.0391 AC: 5953 AN: 152288 Hom.: 302 Cov.: 32 AF XY: 0.0422 AC XY: 3140 AN XY: 74470

African (AFR) AF: 0.0785 AC: 3261 AN: 41566

American (AMR) AF: 0.0223 AC: 341 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.201 AC: 1040 AN: 5170

South Asian (SAS) AF: 0.147 AC: 706 AN: 4818

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10614

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00417 AC: 284 AN: 68034

Other (OTH) AF: 0.0303 AC: 64 AN: 2112

Alfa AF: 0.0322 Hom.: 25

Bravo AF: 0.0406

Asia WGS AF: 0.165 AC: 573 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.68
PhyloP100		-1.6
PromoterAI		0.0025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs130002; hg19: chr16-3827931; COSMIC: COSV52117524; COSMIC: COSV52117524;