17-76007381-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001988.4(EVPL):​c.5824G>T​(p.Gly1942Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1942R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

14
3
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EVPLNM_001988.4 linkc.5824G>T p.Gly1942Trp missense_variant Exon 22 of 22 ENST00000301607.8 NP_001979.2 Q92817
EVPLNM_001320747.2 linkc.5890G>T p.Gly1964Trp missense_variant Exon 22 of 22 NP_001307676.1 Q92817K7EKI0B7ZLH8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EVPLENST00000301607.8 linkc.5824G>T p.Gly1942Trp missense_variant Exon 22 of 22 1 NM_001988.4 ENSP00000301607.3 Q92817
EVPLENST00000586740.1 linkc.5890G>T p.Gly1964Trp missense_variant Exon 22 of 22 1 ENSP00000465630.1 K7EKI0
EVPLENST00000589231.1 linkc.61G>T p.Gly21Trp missense_variant Exon 1 of 2 3 ENSP00000467717.1 K7EQ87
EVPLENST00000587569.5 linkn.6293G>T non_coding_transcript_exon_variant Exon 20 of 20 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1446378
Hom.:
0
Cov.:
30
AF XY:
0.00000140
AC XY:
1
AN XY:
716802
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:
0.0000234
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.31
T;T;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
3.2
.;M;.
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-4.8
.;D;.
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;.
Vest4
0.86, 0.96
MutPred
0.93
.;Loss of disorder (P = 0.0337);.;
MVP
0.98
MPC
0.81
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.71
gMVP
0.88

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.

Other links and lift over

dbSNP: rs201057026; hg19: chr17-74003462; COSMIC: COSV56913634; COSMIC: COSV56913634; API