rs130025

Positions:

• chr16-3782958-C-A
• chr16-3782958-C-G
• chr16-3782958-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000262367.10(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 ENST00000262367.10 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.332

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREBBP	NM_004380.3	c.1331-32G>T		intron_variant		ENST00000262367.10	NP_004371.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREBBP	ENST00000262367.10	c.1331-32G>T		intron_variant		1	NM_004380.3	ENSP00000262367	P1
CREBBP	ENST00000382070.7	c.1217-32G>T		intron_variant		1		ENSP00000371502
CREBBP	ENST00000635753.1	n.64-32G>T		intron_variant, non_coding_transcript_variant		5
CREBBP	ENST00000636002.1	n.44-32G>T		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.0316 AC: 7935 AN: 250956 Hom.: 691 AF XY: 0.0265 AC XY: 3600 AN XY: 135688

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 SAS exome AF: 0.0135

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

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.0232

Gnomad4 ASJ exome AF: 0.0631

Gnomad4 EAS exome AF: 0.0237

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00929

Gnomad4 OTH exome AF: 0.0335

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

Gnomad4 AFR AF: 0.272

Gnomad4 AMR AF: 0.0434

Gnomad4 ASJ AF: 0.0666

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00123

Gnomad4 NFE AF: 0.00944

Gnomad4 OTH AF: 0.0763

Alfa AF: 0.0271 Hom.: 56

Bravo AF: 0.0996

Asia WGS AF: 0.0380 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.8
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs130025; hg19: chr16-3832959;