Variant 17-76007222-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001988.4(EVPL):c.5983G>A(p.Glu1995Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,412,250 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: not found (cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.38

Variant links:

Genes affected

EVPL (HGNC:3503): (envoplakin) This gene encodes a member of the plakin family of proteins that forms a component of desmosomes and the epidermal cornified envelope. This gene is located in the tylosis oesophageal cancer locus on chromosome 17q25, and its deletion is associated with both familial and sporadic forms of oesophageal squamous cell carcinoma. Patients suffering from the autoimmune mucocutaneous disorder, paraneoplastic pemphigus, develop antibodies against the encoded protein. [provided by RefSeq, Jul 2016]

EVPL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36404496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVPL	NM_001988.4 link	c.5983G>A	p.Glu1995Lys	missense_variant	22/22	ENST00000301607.8	NP_001979.2	Q92817
EVPL	NM_001320747.2 link	c.6049G>A	p.Glu2017Lys	missense_variant	22/22		NP_001307676.1	Q92817K7EKI0B7ZLH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EVPL	ENST00000301607.8 link	c.5983G>A	p.Glu1995Lys	missense_variant	22/22	1	NM_001988.4	ENSP00000301607.3	Q92817
EVPL	ENST00000586740.1 link	c.6049G>A	p.Glu2017Lys	missense_variant	22/22	1		ENSP00000465630.1	K7EKI0
EVPL	ENST00000589231.1 link	c.220G>A	p.Glu74Lys	missense_variant	1/2	3		ENSP00000467717.1	K7EQ87
EVPL	ENST00000587569.5 link	n.6452G>A		non_coding_transcript_exon_variant	20/20	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000465

AC:

AN:

215246

Hom.:

AF XY:

0.00000863

AC XY:

AN XY:

115844

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:

0.0000408

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000496

AC:

AN:

1412250

Hom.:

Cov.:

AF XY:

0.00000860

AC XY:

AN XY:

697920

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:

0.0000874

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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 07, 2023

The c.5983G>A (p.E1995K) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a G to A substitution at nucleotide position 5983, causing the glutamic acid (E) at amino acid position 1995 to be replaced by a lysine (K). 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

0.28

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

T;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.8

.;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.9

.;N;.

REVEL

Benign

0.28

Sift

Uncertain

0.0080

.;D;.

Sift4G

Uncertain

0.019

D;D;D

Polyphen

0.95

.;P;.

Vest4

0.59, 0.64

MutPred

0.42

.;Gain of MoRF binding (P = 0.0018);.;

MVP

0.78

MPC

0.48

ClinPred

0.94

GERP RS

5.5

Varity_R

0.59

gMVP

0.69

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