rs130008

Variant names:

• chr16-3731951-C-G
• rs130008
• NM_004380.3:c.4729-14G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-3731951-C-G
• chr16-3731951-C-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.4729-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,614,196 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (313 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.509
• Publications: 6 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=-0.81).
• BP6: Variant 16-3731951-C-G is Benign according to our data. Variant chr16-3731951-C-G is described in ClinVar as Benign. ClinVar VariationId is 158381.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 = 0.0117 (1778/152334) while in subpopulation NFE AF = 0.0197 (1343/68022). AF 95% confidence interval is 0.0189. There are 18 homozygotes in GnomAd4. There are 842 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1778 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.4729-14G>C		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.4615-14G>C		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.4729-14G>C		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.4615-14G>C		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000571763.5	TSL:2	n.519-14G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1778 AN: 152216 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0145

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0197

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0110 AC: 2731 AN: 249022 AF XY: 0.0110

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00399

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.00996

GnomAD4 exome AF: 0.0184 AC: 26873 AN: 1461862 Hom.: 313 Cov.: 33 AF XY: 0.0177 AC XY: 12862 AN XY: 727232

African (AFR) AF: 0.00257 AC: 86 AN: 33480

American (AMR) AF: 0.00445 AC: 199 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00214 AC: 185 AN: 86254

European-Finnish (FIN) AF: 0.0155 AC: 827 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5750

European-Non Finnish (NFE) AF: 0.0222 AC: 24670 AN: 1112010

Other (OTH) AF: 0.0134 AC: 811 AN: 60396

GnomAD4 genome AF: 0.0117 AC: 1778 AN: 152334 Hom.: 18 Cov.: 32 AF XY: 0.0113 AC XY: 842 AN XY: 74490

African (AFR) AF: 0.00378 AC: 157 AN: 41576

American (AMR) AF: 0.00575 AC: 88 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4830

European-Finnish (FIN) AF: 0.0145 AC: 154 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0197 AC: 1343 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00672 Hom.: 4

Bravo AF: 0.0110

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.10
DANN	Benign	0.52
PhyloP100		-0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs130008; hg19: chr16-3781952;