rs130008

Positions:

• chr16-3731951-C-G
• chr16-3731951-C-T

Variant summary

Our verdict is Benign. Variant got -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 splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.509

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=-0.81).
• BP6: Variant 16-3731951-C-G is Benign according to our data. Variant chr16-3731951-C-G is described in ClinVar as [Benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1778 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREBBP	NM_004380.3	c.4729-14G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262367.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREBBP	ENST00000262367.10	c.4729-14G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004380.3	P1
CREBBP	ENST00000382070.7	c.4615-14G>C		splice_polypyrimidine_tract_variant, intron_variant		1
CREBBP	ENST00000571763.5	n.519-14G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
CREBBP	ENST00000576720.1	n.3552-14G>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.0110 AC: 2731 AN: 249022 Hom.: 18 AF XY: 0.0110 AC XY: 1488 AN XY: 134806

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 SAS exome AF: 0.00199

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

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.00306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00214

Gnomad4 FIN exome AF: 0.0155

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0134

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

Gnomad4 AFR AF: 0.00378

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0145

Gnomad4 NFE AF: 0.0197

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00672 Hom.: 4

Bravo AF: 0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Rubinstein-Taybi syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

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	-0.81
CADD	Benign	0.10
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs130008; hg19: chr16-3781952;