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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001429.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	NM_001429.4	MANE Select	c.6627_6638delCCAGTTCCAGCA	p.Asn2209_Gln2213delinsLys	disruptive_inframe_deletion	Exon 31 of 31	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.6549_6560delCCAGTTCCAGCA	p.Asn2183_Gln2187delinsLys	disruptive_inframe_deletion	Exon 30 of 30	NP_001349772.1	A0A669KB12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EP300	ENST00000263253.9	TSL:1 MANE Select	c.6627_6638delCCAGTTCCAGCA	p.Asn2209_Gln2213delinsLys	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.6657_6668delCCAGTTCCAGCA	p.Asn2219_Gln2223delinsLys	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000586141.1
	EP300	ENST00000715703.1		c.6627_6638delCCAGTTCCAGCA	p.Asn2209_Gln2213delinsLys	disruptive_inframe_deletion	Exon 31 of 31	ENSP00000520505.1	Q09472

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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
1	1	2	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (4)
-	-	1	EP300-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	See cases (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;