NM_004380.3:c.1331-32G>T

Variant names:

• chr16-3782958-C-A
• rs130025
• NM_004380.3:c.1331-32G>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.1331-32G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,613,734 control chromosomes in the GnomAD database, including 3,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (1585 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1594 hom.)
• Consequence: CREBBP NM_004380.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.332
• 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=-0.89).
• BP6: Variant 16-3782958-C-A is Benign according to our data. Variant chr16-3782958-C-A is described in ClinVar as Benign. ClinVar VariationId is 1238727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 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.1331-32G>T		intron	N/A	NP_004371.2
	CREBBP	NM_001079846.1		c.1217-32G>T		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.1331-32G>T		intron	N/A	ENSP00000262367.5
	CREBBP	ENST00000382070.7	TSL:1	c.1217-32G>T		intron	N/A	ENSP00000371502.3
	CREBBP	ENST00000635753.1	TSL:5	n.64-32G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0860 AC: 13061 AN: 151934 Hom.: 1574 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0434

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.0771

GnomAD2 exomes AF: 0.0316 AC: 7935 AN: 250956 AF XY: 0.0265

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0640

Gnomad EAS exome AF: 0.0164

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.0102

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0184 AC: 26883 AN: 1461682 Hom.: 1594 Cov.: 31 AF XY: 0.0175 AC XY: 12758 AN XY: 727134

African (AFR) AF: 0.279 AC: 9337 AN: 33466

American (AMR) AF: 0.0232 AC: 1037 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 1650 AN: 26134

East Asian (EAS) AF: 0.0237 AC: 941 AN: 39700

South Asian (SAS) AF: 0.0134 AC: 1153 AN: 86206

European-Finnish (FIN) AF: 0.00187 AC: 100 AN: 53410

Middle Eastern (MID) AF: 0.0536 AC: 309 AN: 5768

European-Non Finnish (NFE) AF: 0.00929 AC: 10331 AN: 1111924

Other (OTH) AF: 0.0335 AC: 2025 AN: 60394

GnomAD4 genome AF: 0.0863 AC: 13119 AN: 152052 Hom.: 1585 Cov.: 32 AF XY: 0.0819 AC XY: 6086 AN XY: 74318

African (AFR) AF: 0.272 AC: 11269 AN: 41422

American (AMR) AF: 0.0434 AC: 662 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 231 AN: 3468

East Asian (EAS) AF: 0.0131 AC: 68 AN: 5182

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4818

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10576

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00944 AC: 642 AN: 68000

Other (OTH) AF: 0.0763 AC: 161 AN: 2110

Alfa AF: 0.0271 Hom.: 56

Bravo AF: 0.0996

Asia WGS AF: 0.0380 AC: 134 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	-0.89
CADD	Benign	2.8
DANN	Benign	0.55
PhyloP100		0.33
PromoterAI		-0.029	Neutral
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: rs130025; hg19: chr16-3832959;