Variant 17-19285620-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_014964.5(EPN2):c.596C>T(p.Ser199Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,384,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

EPN2
NM_014964.5 missense, splice_region

Scores

Splicing: ADA: 0.9943

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EPN2	NM_014964.5 linkuse as main transcript	c.596C>T	p.Ser199Leu	missense_variant, splice_region_variant	4/11	ENST00000314728.10	NP_055779.2
EPN2	NM_001102664.2 linkuse as main transcript	c.-89-24265C>T		intron_variant			NP_001096134.1
EPN2	NM_148921.4 linkuse as main transcript	c.595+1906C>T		intron_variant			NP_683723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPN2	ENST00000314728.10 linkuse as main transcript	c.596C>T	p.Ser199Leu	missense_variant, splice_region_variant	4/11	1	NM_014964.5	ENSP00000320543	P3	O95208-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000433

AC:

AN:

1384988

Hom.:

Cov.:

AF XY:

0.00000586

AC XY:

AN XY:

682066

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000560

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000856

AC:

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

Jun 10, 2022

The c.596C>T (p.S199L) alteration is located in exon 4 (coding exon 2) of the EPN2 gene. This alteration results from a C to T substitution at nucleotide position 596, causing the serine (S) at amino acid position 199 to be replaced by a leucine (L). 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

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.11

Sift

Benign

0.050

D;T

Sift4G

Uncertain

0.054

T;T

Polyphen

0.74

P;P

Vest4

0.56

MVP

0.60

MPC

0.67

ClinPred

0.85

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.060

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