Variant 17-76007128-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001988.4(EVPL):c.6077C>A(p.Pro2026His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,488,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

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=0.11741912).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EVPL	NM_001988.4 link	c.6077C>A	p.Pro2026His	missense_variant	22/22	ENST00000301607.8	NP_001979.2	Q92817
EVPL	NM_001320747.2 link	c.6143C>A	p.Pro2048His	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.6077C>A	p.Pro2026His	missense_variant	22/22	1	NM_001988.4	ENSP00000301607.3	Q92817
EVPL	ENST00000586740.1 link	c.6143C>A	p.Pro2048His	missense_variant	22/22	1		ENSP00000465630.1	K7EKI0
EVPL	ENST00000589231.1 link	c.314C>A	p.Pro105His	missense_variant	1/2	3		ENSP00000467717.1	K7EQ87
EVPL	ENST00000587569.5 link	n.6546C>A		non_coding_transcript_exon_variant	20/20	2

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000827

AC:

AN:

169366

Hom.:

AF XY:

0.000100

AC XY:

AN XY:

89718

show subpopulations

Gnomad AFR exome

AF:

0.0000669

Gnomad AMR exome

AF:

0.0000991

Gnomad ASJ exome

AF:

0.000296

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000256

GnomAD4 exome

AF:

0.000114

AC:

152

AN:

1335742

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

651626

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000602

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000819

Gnomad4 OTH exome

AF:

0.000400

GnomAD4 genome

AF:

0.000374

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000423

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

Dec 22, 2023

The c.6077C>A (p.P2026H) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a C to A substitution at nucleotide position 6077, causing the proline (P) at amino acid position 2026 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

0.10

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;T;.

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.68

T;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.5

.;M;.

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.4

.;D;.

REVEL

Benign

0.15

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

.;D;.

Vest4

0.54, 0.57

MVP

0.84

MPC

0.65

ClinPred

0.47

GERP RS

4.4

Varity_R

0.39

gMVP

0.48

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