dbSNP rs201833287: EVPL:p.Pro2026Arg (chr17-76007128-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

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

The NM_001988.4(EVPL):c.6077C>G(p.Pro2026Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000299 in 1,335,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2026H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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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=0.29795015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVPL	NM_001988.4 link	c.6077C>G	p.Pro2026Arg	missense_variant	Exon 22 of 22	ENST00000301607.8	NP_001979.2	Q92817
EVPL	NM_001320747.2 link	c.6143C>G	p.Pro2048Arg	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.6077C>G	p.Pro2026Arg	missense_variant	Exon 22 of 22	1	NM_001988.4	ENSP00000301607.3	Q92817
EVPL	ENST00000586740.1 link	c.6143C>G	p.Pro2048Arg	missense_variant	Exon 22 of 22	1		ENSP00000465630.1	K7EKI0
EVPL	ENST00000589231.1 link	c.314C>G	p.Pro105Arg	missense_variant	Exon 1 of 2	3		ENSP00000467717.1	K7EQ87
EVPL	ENST00000587569.5 link	n.6546C>G		non_coding_transcript_exon_variant	Exon 20 of 20	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000299

AC:

AN:

1335742

Hom.:

Cov.:

AF XY:

0.00000307

AC XY:

AN XY:

651626

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000545

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

T;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.64

T;T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.5

.;M;.

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.1

.;D;.

REVEL

Benign

0.079

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.034

.;B;.

Vest4

0.22, 0.25

MutPred

0.36

.;Gain of MoRF binding (P = 0.003);.;

MVP

0.78

MPC

0.21

ClinPred

0.96

GERP RS

4.4

Varity_R

0.28

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over