rs186198699

chr22-41140266-C-Gchr22-41140266-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001429.4(EP300):c.1878+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,575,552 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: EP300 NM_001429.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.300

Genes affected

EP300 (HGNC:3373): (E1A binding protein p300) This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 22-41140266-C-G is Benign according to our data. Variant chr22-41140266-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 210938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41140266-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EP300	NM_001429.4	c.1878+9C>G		intron_variant		ENST00000263253.9
EP300	NM_001362843.2	c.1878+9C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EP300	ENST00000263253.9	c.1878+9C>G		intron_variant		1	NM_001429.4	P2

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00442

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251476 Hom.: 0 AF XY: 0.000250 AC XY: 34 AN XY: 135910

Gnomad AFR exome AF: 0.00492

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000189 AC: 269 AN: 1423340 Hom.: 2 Cov.: 25 AF XY: 0.000173 AC XY: 123 AN XY: 710590

Gnomad4 AFR exome AF: 0.00650

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000702

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000743

Gnomad4 OTH exome AF: 0.000406

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74410

Gnomad4 AFR AF: 0.00441

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000513 Hom.: 0

Bravo AF: 0.00172

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	EP300: BS1 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 12, 2014

- -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	2.0
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs186198699; hg19: chr22-41536270;