22-41178373-C-A

Position:

• chr22-41178373-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000263253.9(EP300):​c.6662C>A​(p.Pro2221Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2221L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EP300 ENST00000263253.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.103

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]

(HGNC:):

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

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41178373-C-A is Pathogenic according to our data. Variant chr22-41178373-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 6881.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2090106). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EP300	NM_001429.4	c.6662C>A	p.Pro2221Gln	missense_variant	31/31	ENST00000263253.9	NP_001420.2
EP300	NM_001362843.2	c.6584C>A	p.Pro2195Gln	missense_variant	30/30		NP_001349772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EP300	ENST00000263253.9	c.6662C>A	p.Pro2221Gln	missense_variant	31/31	1	NM_001429.4	ENSP00000263253	P2
	ENST00000415054.1	n.82+4690G>T		intron_variant, non_coding_transcript_variant		3
EP300-AS1	ENST00000420537.1	n.224-3549G>T		intron_variant, non_coding_transcript_variant		3
EP300	ENST00000674155.1	c.6584C>A	p.Pro2195Gln	missense_variant	30/30			ENSP00000501078	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Carcinoma of colon Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.5
DANN	Benign	0.68
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.42	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.17
Sift	Benign	0.60	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.25		Loss of loop (P = 0.0153);
MVP		0.66
ClinPred		0.054	T
GERP RS		3.2
Varity_R		0.039
gMVP		0.25

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: rs28937578; hg19: chr22-41574377; COSMIC: COSV54338224; COSMIC: COSV54338224;