2-148754002-G-A

Variant names:

• chr2-148754002-G-A
• rs1683128517
• NM_015630.4:c.535G>A

Variant summary

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

The NM_015630.4(EPC2):​c.535G>A​(p.Val179Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: EPC2 NM_015630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.69

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31016427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4	c.535G>A	p.Val179Met	missense_variant	Exon 4 of 14	ENST00000258484.11	NP_056445.3
EPC2	XM_011510941.3	c.535G>A	p.Val179Met	missense_variant	Exon 4 of 14		XP_011509243.1
EPC2	XM_011510943.4	c.268G>A	p.Val90Met	missense_variant	Exon 3 of 13		XP_011509245.1
EPC2	XM_047443897.1	c.187G>A	p.Val63Met	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.535G>A	p.Val179Met	missense_variant	Exon 4 of 14	1	NM_015630.4	ENSP00000258484.6
EPC2	ENST00000397424.2	c.322G>A	p.Val108Met	missense_variant	Exon 4 of 5	3		ENSP00000380569.2
EPC2	ENST00000457184.5	c.463G>A	p.Val155Met	missense_variant	Exon 5 of 5	5		ENSP00000415543.2
EPC2	ENST00000491099.1	n.108G>A		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.535G>A (p.V179M) alteration is located in exon 4 (coding exon 4) of the EPC2 gene. This alteration results from a G to A substitution at nucleotide position 535, causing the valine (V) at amino acid position 179 to be replaced by a methionine (M). 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	Benign	0.19
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.4	.;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.050	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.97	.;D;.
Vest4		0.51
MutPred		0.30		.;Gain of MoRF binding (P = 0.0956);.;
MVP		0.26
MPC		0.95
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.13
gMVP		0.37

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: rs1683128517; hg19: chr2-149511571; COSMIC: COSV99310220;