Genetic Variant EVPL:p.Arg2019His (chr17-76007149-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001988.4(EVPL):c.6056G>A(p.Arg2019His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000594 in 1,346,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000059 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.173

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.071079314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVPL	NM_001988.4 link	c.6056G>A	p.Arg2019His	missense_variant	Exon 22 of 22	ENST00000301607.8	NP_001979.2	Q92817
EVPL	NM_001320747.2 link	c.6122G>A	p.Arg2041His	missense_variant	Exon 22 of 22		NP_001307676.1	Q92817K7EKI0B7ZLH8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EVPL	ENST00000301607.8 link	c.6056G>A	p.Arg2019His	missense_variant	Exon 22 of 22	1	NM_001988.4	ENSP00000301607.3	Q92817
EVPL	ENST00000586740.1 link	c.6122G>A	p.Arg2041His	missense_variant	Exon 22 of 22	1		ENSP00000465630.1	K7EKI0
EVPL	ENST00000589231.1 link	c.293G>A	p.Arg98His	missense_variant	Exon 1 of 2	3		ENSP00000467717.1	K7EQ87
EVPL	ENST00000587569.5 link	n.6525G>A		non_coding_transcript_exon_variant	Exon 20 of 20	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000172

AC:

AN:

174372

Hom.:

AF XY:

0.0000217

AC XY:

AN XY:

92294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000482

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000594

AC:

AN:

1346120

Hom.:

Cov.:

AF XY:

0.00000761

AC XY:

AN XY:

657366

show subpopulations

Gnomad4 AFR exome

AF:

0.0000333

Gnomad4 AMR exome

AF:

0.0000348

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000781

Gnomad4 SAS exome

AF:

0.0000293

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.48e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000835

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6056G>A (p.R2019H) 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 6056, causing the arginine (R) at amino acid position 2019 to be replaced by a histidine (H). 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

0.068

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.076

T;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.071

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.2

.;N;.

REVEL

Benign

0.023

Sift

Benign

0.17

.;T;.

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0040

.;B;.

Vest4

0.090, 0.15

MutPred

0.37

.;Loss of MoRF binding (P = 0.0219);.;

MVP

0.66

MPC

0.23

ClinPred

0.12

GERP RS

0.99

Varity_R

0.040

gMVP

0.34

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