rs587778256

Variant names:

• chr22-41178336-AACCAGTTCCAGC-A
• rs587778256
• NM_001429.4:c.6627_6638delCCAGTTCCAGCA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM4 PP3 BP6 BS2

The NM_001429.4(EP300):​c.6627_6638delCCAGTTCCAGCA​(p.Asn2209_Gln2213delinsLys) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,614,128 control chromosomes in the GnomAD database, including 5 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: EP300 NM_001429.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:10 O:1
• Conservation: PhyloP100: 7.86
• Publications: 2 publications found

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]

EP300-AS1 (HGNC:50504): (EP300 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001429.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 22-41178336-AACCAGTTCCAGC-A is Benign according to our data. Variant chr22-41178336-AACCAGTTCCAGC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 253313.
• BS2: High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EP300	NM_001429.4	c.6627_6638delCCAGTTCCAGCA	p.Asn2209_Gln2213delinsLys	disruptive_inframe_deletion	Exon 31 of 31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.6549_6560delCCAGTTCCAGCA	p.Asn2183_Gln2187delinsLys	disruptive_inframe_deletion	Exon 30 of 30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.6627_6638delCCAGTTCCAGCA	p.Asn2209_Gln2213delinsLys	disruptive_inframe_deletion	Exon 31 of 31	1	NM_001429.4	ENSP00000263253.7

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00155 AC: 390 AN: 251338 AF XY: 0.00149

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00188 AC: 2748 AN: 1461886 Hom.: 5 AF XY: 0.00189 AC XY: 1371 AN XY: 727244

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00219 AC: 2433 AN: 1112006

Other (OTH) AF: 0.00204 AC: 123 AN: 60396

GnomAD4 genome AF: 0.00166 AC: 252 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74442

African (AFR) AF: 0.000409 AC: 17 AN: 41542

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 67990

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00327 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00262

EpiControl AF: 0.00196

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29506490, 33337535) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EP300: PM4, BS1, BS2 -

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency Pathogenic:1 Uncertain:1 Benign:2

Oct 20, 2022

Dr. med. U. Finckh, Human Genetics, Eurofins MVZ

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This EP300 variant deletes 12 nucleotides leading to an inframe deletion of codons 2209-2213 and insertion of 1 Lysine. It has been described occurring de novo in patients with Rubinstein-Taybi syndrome (PMID: 29506490, 33337535) but also is present in approx. 0.6% of the european general population. Either the variant was found randomly and without causal relationship in affected patients or it predisposes - seeming less likely - to a low-penetrance / variable-expression form of the disease, possibly influenced by additional factors. Internal data: Heterozygous in a proband with early childhood autism spectrum disorder not displaying any other obvious similarities to Rubinstein-Taybi syndrome. Subsequently, the variant was also detected in the unaffected father. We classify the variant as uncertain. -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2016

Fundacion Rioja Salud, Center for Biomedical Research (CIBIR)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 23, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

See cases Benign:1

Jan 14, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: BS1, BS2 -

EP300-related disorder Benign:1

Jul 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=41/159	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587778256; hg19: chr22-41574340; COSMIC: COSV54329774;