Genetic Variant EPC2:p.Ile143Met (chr2-148743737-T-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015630.4(EPC2):c.429T>G(p.Ile143Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I143V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPC2
NM_015630.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.364

Variant links:

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]

EPC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099288285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4 link	c.429T>G	p.Ile143Met	missense_variant	Exon 3 of 14	ENST00000258484.11	NP_056445.3	Q52LR7
EPC2	XM_011510941.3 link	c.429T>G	p.Ile143Met	missense_variant	Exon 3 of 14		XP_011509243.1
EPC2	XM_011510943.4 link	c.162T>G	p.Ile54Met	missense_variant	Exon 2 of 13		XP_011509245.1
EPC2	XM_047443897.1 link	c.81T>G	p.Ile27Met	missense_variant	Exon 2 of 13		XP_047299853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPC2	ENST00000258484.11 link	c.429T>G	p.Ile143Met	missense_variant	Exon 3 of 14	1	NM_015630.4	ENSP00000258484.6	Q52LR7
EPC2	ENST00000397424.2 link	c.216T>G	p.Ile72Met	missense_variant	Exon 3 of 5	3		ENSP00000380569.2	C9J1X4
EPC2	ENST00000457184.5 link	c.357T>G	p.Ile119Met	missense_variant	Exon 4 of 5	5		ENSP00000415543.2	E7ETK1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000422

AC:

AN:

236872

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449884

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32590

American (AMR)

AF:

0.00

AC:

AN:

42414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

38982

South Asian (SAS)

AF:

0.00

AC:

AN:

83926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107460

Other (OTH)

AF:

0.0000334

AC:

AN:

59838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41590

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.429T>G (p.I143M) alteration is located in exon 3 (coding exon 3) of the EPC2 gene. This alteration results from a T to G substitution at nucleotide position 429, causing the isoleucine (I) at amino acid position 143 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

0.088

BayesDel_addAF

Benign

-0.00054

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.074

.;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.47

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.0080

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

.;N;.

PhyloP100

0.36

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.62

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.66

T;T;T

Sift4G

Benign

0.59

T;T;T

Polyphen

0.0020

.;B;.

Vest4

0.62

MVP

0.86

MPC

0.35

ClinPred

0.11

GERP RS

2.8

Varity_R

0.049

gMVP

0.49

Mutation Taster

=58/42

polymorphism

(source)

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

Below is the list of publications found by LitVar for variant 2:148743737 T>G . It may be empty.

2-148743737-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over