NM_004380.3:c.1676+18A>T

Variant names:

• chr16-3781186-T-A
• rs130018
• NM_004380.3:c.1676+18A>T

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.1676+18A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 1,603,678 control chromosomes in the GnomAD database, including 2,360 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (1152 hom., cov: 32)
  • Exomes 𝑓: 0.017 (1208 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.497
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-3781186-T-A is Benign according to our data. Variant chr16-3781186-T-A is described in ClinVar as Benign. ClinVar VariationId is 95028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREBBP	NM_004380.3	MANE Select	c.1676+18A>T		intron	N/A	NP_004371.2	Q92793-1
	CREBBP	NM_001079846.1		c.1562+18A>T		intron	N/A	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.1676+18A>T		intron	N/A	ENSP00000262367.5	Q92793-1
	CREBBP	ENST00000382070.7	TSL:1	c.1562+18A>T		intron	N/A	ENSP00000371502.3	Q92793-2
	CREBBP	ENST00000570939.2	TSL:5	c.281+18A>T		intron	N/A	ENSP00000461002.2	I3L466

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11386 AN: 152084 Hom.: 1144 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0665

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.0288 AC: 7232 AN: 251126 AF XY: 0.0244

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0192

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.0164

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.00988

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0173 AC: 25088 AN: 1451476 Hom.: 1208 Cov.: 29 AF XY: 0.0166 AC XY: 11981 AN XY: 722788

African (AFR) AF: 0.239 AC: 7932 AN: 33252

American (AMR) AF: 0.0222 AC: 991 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 1634 AN: 26046

East Asian (EAS) AF: 0.0236 AC: 937 AN: 39620

South Asian (SAS) AF: 0.0133 AC: 1144 AN: 85962

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53406

Middle Eastern (MID) AF: 0.0518 AC: 298 AN: 5748

European-Non Finnish (NFE) AF: 0.00920 AC: 10149 AN: 1102666

Other (OTH) AF: 0.0317 AC: 1903 AN: 60082

GnomAD4 genome AF: 0.0751 AC: 11437 AN: 152202 Hom.: 1152 Cov.: 32 AF XY: 0.0713 AC XY: 5307 AN XY: 74422

African (AFR) AF: 0.232 AC: 9630 AN: 41462

American (AMR) AF: 0.0410 AC: 628 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0665 AC: 231 AN: 3472

East Asian (EAS) AF: 0.0133 AC: 69 AN: 5188

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10614

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00944 AC: 642 AN: 68024

Other (OTH) AF: 0.0715 AC: 151 AN: 2112

Alfa AF: 0.0445 Hom.: 96

Bravo AF: 0.0870

Asia WGS AF: 0.0370 AC: 129 AN: 3478

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	Rubinstein-Taybi syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.1
DANN	Benign	0.55
PhyloP100		-0.50
PromoterAI		0.010	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: rs130018; hg19: chr16-3831187;