Variant 17-19283159-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014964.5(EPN2):c.40G>A(p.Val14Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,872 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: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

EPN2
NM_014964.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.94

Variant links:

Genes affected

EPN2 (HGNC:18639): (epsin 2) This gene encodes a protein which interacts with clathrin and adaptor-related protein complex 2, alpha 1 subunit. The protein is found in a brain-derived clathrin-coated vesicle fraction and localizes to the peri-Golgi region and the cell periphery. The protein is thought to be involved in clathrin-mediated endocytosis. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

EPN2 links:

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ACMG classification

Classification made for transcript

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, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EPN2	NM_014964.5 linkuse as main transcript	c.40G>A	p.Val14Met	missense_variant	3/11	ENST00000314728.10	NP_055779.2
EPN2	NM_148921.4 linkuse as main transcript	c.40G>A	p.Val14Met	missense_variant	3/10		NP_683723.2
EPN2	NM_001102664.2 linkuse as main transcript	c.-89-26726G>A		intron_variant			NP_001096134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPN2	ENST00000314728.10 linkuse as main transcript	c.40G>A	p.Val14Met	missense_variant	3/11	1	NM_014964.5	ENSP00000320543	P3	O95208-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460680

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.40G>A (p.V14M) alteration is located in exon 3 (coding exon 1) of the EPN2 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

.;.;D;.;.;.;.;.;.;T;.;T;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;.;D;.;D;D

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.5

.;.;M;M;.;.;.;.;.;.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-2.7

.;.;D;D;.;.;D;.;.;.;D;D;.

REVEL

Uncertain

0.53

Sift

Uncertain

0.0010

.;.;D;D;.;.;D;.;.;.;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;.;D;D;D;.;D;D;D;D

Polyphen

0.98, 0.96

.;.;D;.;.;.;.;.;.;.;.;D;.

Vest4

0.89, 0.91, 0.82, 0.86

MVP

0.72

MPC

1.0

ClinPred

0.98

GERP RS

5.8

Varity_R

0.64

gMVP

0.76

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