chr22-41141230-G-T

Variant names:

• chr22-41141230-G-T
• rs6002267
• NM_001429.4:c.2053+8G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001429.4(EP300):​c.2053+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 1,613,534 control chromosomes in the GnomAD database, including 797,225 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.97 (71357 hom., cov: 33)
  • Exomes 𝑓: 1.0 (725868 hom.)
• Consequence: EP300 NM_001429.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001963
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.06
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-41141230-G-T is Benign according to our data. Variant chr22-41141230-G-T is described in ClinVar as Benign. ClinVar VariationId is 93732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.2053+8G>T		splice_region intron	N/A	NP_001420.2	Q09472
	EP300	NM_001362843.2		c.2053+8G>T		splice_region intron	N/A	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.2053+8G>T		splice_region intron	N/A	ENSP00000263253.7	Q09472
	EP300	ENST00000916082.1		c.2053+8G>T		splice_region intron	N/A	ENSP00000586141.1
	EP300	ENST00000715703.1		c.2053+8G>T		splice_region intron	N/A	ENSP00000520505.1	Q09472

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147104 AN: 152202 Hom.: 71306 Cov.: 33

Gnomad AFR AF: 0.883

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.988

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.980

GnomAD2 exomes AF: 0.991 AC: 249073 AN: 251244 AF XY: 0.994

Gnomad AFR exome AF: 0.878

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.997 AC: 1456183 AN: 1461214 Hom.: 725868 Cov.: 38 AF XY: 0.997 AC XY: 724801 AN XY: 726910

African (AFR) AF: 0.874 AC: 29226 AN: 33458

American (AMR) AF: 0.996 AC: 44503 AN: 44702

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26132 AN: 26132

East Asian (EAS) AF: 1.00 AC: 39692 AN: 39692

South Asian (SAS) AF: 1.00 AC: 86158 AN: 86176

European-Finnish (FIN) AF: 1.00 AC: 53406 AN: 53406

Middle Eastern (MID) AF: 0.997 AC: 5753 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111372 AN: 1111508

Other (OTH) AF: 0.993 AC: 59941 AN: 60372

GnomAD4 genome AF: 0.966 AC: 147214 AN: 152320 Hom.: 71357 Cov.: 33 AF XY: 0.968 AC XY: 72082 AN XY: 74490

African (AFR) AF: 0.883 AC: 36676 AN: 41538

American (AMR) AF: 0.988 AC: 15122 AN: 15300

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5193 AN: 5194

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68031 AN: 68050

Other (OTH) AF: 0.980 AC: 2068 AN: 2110

Alfa AF: 0.983 Hom.: 33510

Bravo AF: 0.962

Asia WGS AF: 0.994 AC: 3456 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (2)
-	-	1	Menke-Hennekam syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.44
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs6002267; hg19: chr22-41537234;