Genetic Variant NM_015630.4:c.1046C>G (chr2-148765052-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015630.4(EPC2):c.1046C>G(p.Ser349Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000621 in 1,609,936 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EPC2
NM_015630.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17301166).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4 link	c.1046C>G	p.Ser349Cys	missense_variant	Exon 7 of 14	ENST00000258484.11	NP_056445.3	Q52LR7
EPC2	XM_011510941.3 link	c.1046C>G	p.Ser349Cys	missense_variant	Exon 7 of 14		XP_011509243.1
EPC2	XM_011510943.4 link	c.779C>G	p.Ser260Cys	missense_variant	Exon 6 of 13		XP_011509245.1
EPC2	XM_047443897.1 link	c.698C>G	p.Ser233Cys	missense_variant	Exon 6 of 13		XP_047299853.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPC2	ENST00000258484.11 link	c.1046C>G	p.Ser349Cys	missense_variant	Exon 7 of 14	1	NM_015630.4	ENSP00000258484.6		Q52LR7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247504

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134324

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1457782

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

725204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000676

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:

0.00

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

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

Bravo

AF:

0.000110

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1046C>G (p.S349C) alteration is located in exon 7 (coding exon 7) of the EPC2 gene. This alteration results from a C to G substitution at nucleotide position 1046, causing the serine (S) at amino acid position 349 to be replaced by a cysteine (C). 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

0.067

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.60

M_CAP

Benign

0.0026

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.3

REVEL

Benign

0.13

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.036

Polyphen

0.46

Vest4

0.14

MutPred

0.26

Loss of glycosylation at P354 (P = 0.1256);

MVP

0.17

MPC

0.48

ClinPred

0.40

GERP RS

6.2

Varity_R

0.12

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over