rs1387403265

Variant names:

• chr2-148753967-A-G
• rs1387403265
• NM_015630.4:c.500A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015630.4(EPC2):​c.500A>G​(p.Asp167Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPC2 NM_015630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

Genes affected

EPC2 (HGNC:24543): (enhancer of polycomb homolog 2) Predicted to contribute to histone acetyltransferase activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be part of Piccolo NuA4 histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4	c.500A>G	p.Asp167Gly	missense_variant	Exon 4 of 14	ENST00000258484.11	NP_056445.3
EPC2	XM_011510941.3	c.500A>G	p.Asp167Gly	missense_variant	Exon 4 of 14		XP_011509243.1
EPC2	XM_011510943.4	c.233A>G	p.Asp78Gly	missense_variant	Exon 3 of 13		XP_011509245.1
EPC2	XM_047443897.1	c.152A>G	p.Asp51Gly	missense_variant	Exon 3 of 13		XP_047299853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPC2	ENST00000258484.11	c.500A>G	p.Asp167Gly	missense_variant	Exon 4 of 14	1	NM_015630.4	ENSP00000258484.6
EPC2	ENST00000397424.2	c.287A>G	p.Asp96Gly	missense_variant	Exon 4 of 5	3		ENSP00000380569.2
EPC2	ENST00000457184.5	c.428A>G	p.Asp143Gly	missense_variant	Exon 5 of 5	5		ENSP00000415543.2
EPC2	ENST00000491099.1	n.73A>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459764 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500A>G (p.D167G) alteration is located in exon 4 (coding exon 4) of the EPC2 gene. This alteration results from a A to G substitution at nucleotide position 500, causing the aspartic acid (D) at amino acid position 167 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.6	.;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.026	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.81
MutPred		0.48		.;Loss of stability (P = 0.0125);.;
MVP		0.47
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1387403265; hg19: chr2-149511536;