Genetic Variant EPC2:p.Ser5Phe (chr2-148645031-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015630.4(EPC2):c.14C>T(p.Ser5Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,398,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EPC2
NM_015630.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPC2	NM_015630.4 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 14	ENST00000258484.11	NP_056445.3	Q52LR7
EPC2	XM_011510941.3 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 14		XP_011509243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPC2	ENST00000258484.11 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 14	1	NM_015630.4	ENSP00000258484.6	Q52LR7
EPC2	ENST00000409654.5 link	c.14C>T	p.Ser5Phe	missense_variant	Exon 1 of 3	3		ENSP00000387097.1	E9PBA8
EPC2	ENST00000457184.5 link	c.-50-9C>T		intron_variant	Intron 1 of 4	5		ENSP00000415543.2	E7ETK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000626

AC:

AN:

159746

Hom.:

AF XY:

0.0000118

AC XY:

AN XY:

85018

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:

0.0000431

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1398888

Hom.:

Cov.:

AF XY:

0.00000435

AC XY:

AN XY:

690408

show subpopulations

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:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000186

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14C>T (p.S5F) alteration is located in exon 1 (coding exon 1) of the EPC2 gene. This alteration results from a C to T substitution at nucleotide position 14, causing the serine (S) at amino acid position 5 to be replaced by a phenylalanine (F). 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

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

D;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.17

MetaRNN

Uncertain

0.55

D;D

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.0

D;D

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.61

P;.

Vest4

0.83

MutPred

0.42

Loss of disorder (P = 0.0044);Loss of disorder (P = 0.0044);

MVP

0.31

MPC

3.0

ClinPred

0.99

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.90

gMVP

0.78

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. 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