17-76007141-G-A

Variant summary

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

The NM_001988.4(EVPL):​c.6064C>T​(p.Arg2022Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000831 in 1,492,018 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: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65
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 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=0.15104946).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EVPLNM_001988.4 linkc.6064C>T p.Arg2022Cys missense_variant 22/22 ENST00000301607.8 NP_001979.2 Q92817
EVPLNM_001320747.2 linkc.6130C>T p.Arg2044Cys missense_variant 22/22 NP_001307676.1 Q92817K7EKI0B7ZLH8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EVPLENST00000301607.8 linkc.6064C>T p.Arg2022Cys missense_variant 22/221 NM_001988.4 ENSP00000301607.3 Q92817
EVPLENST00000586740.1 linkc.6130C>T p.Arg2044Cys missense_variant 22/221 ENSP00000465630.1 K7EKI0
EVPLENST00000589231.1 linkc.301C>T p.Arg101Cys missense_variant 1/23 ENSP00000467717.1 K7EQ87
EVPLENST00000587569.5 linkn.6533C>T non_coding_transcript_exon_variant 20/202

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152222
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000816
AC:
14
AN:
171620
Hom.:
0
AF XY:
0.0000882
AC XY:
8
AN XY:
90688
show subpopulations
Gnomad AFR exome
AF:
0.0000662
Gnomad AMR exome
AF:
0.0000982
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000129
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000858
AC:
115
AN:
1339796
Hom.:
0
Cov.:
30
AF XY:
0.0000918
AC XY:
60
AN XY:
653752
show subpopulations
Gnomad4 AFR exome
AF:
0.0000334
Gnomad4 AMR exome
AF:
0.0000704
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000150
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000998
Gnomad4 OTH exome
AF:
0.000109
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152222
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74368
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000839
AC:
10

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 submitterclinical testingAmbry GeneticsMay 11, 2022The c.6064C>T (p.R2022C) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a C to T substitution at nucleotide position 6064, causing the arginine (R) at amino acid position 2022 to be replaced by a cysteine (C). 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
-0.22
T
BayesDel_noAF
Benign
-0.29
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;D;.
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.73
T;T;T
M_CAP
Uncertain
0.094
D
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.74
T
MutationAssessor
Uncertain
2.1
.;M;.
PrimateAI
Benign
0.35
T
PROVEAN
Uncertain
-3.2
.;D;.
REVEL
Benign
0.11
Sift
Uncertain
0.0010
.;D;.
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.0090
.;B;.
Vest4
0.40, 0.43
MVP
0.75
MPC
0.79
ClinPred
0.24
T
GERP RS
3.5
Varity_R
0.21
gMVP
0.60

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: rs369500318; hg19: chr17-74003222; API