dbSNP rs772991578: EVPL:p.Gly2007Ser (chr17-76007186-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001988.4(EVPL):c.6019G>A(p.Gly2007Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000742 in 1,522,168 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

EVPL
NM_001988.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.00

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

EVPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32938874).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001988.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVPL	NM_001988.4	MANE Select	c.6019G>A	p.Gly2007Ser	missense	Exon 22 of 22	NP_001979.2	Q92817
	EVPL	NM_001320747.2		c.6085G>A	p.Gly2029Ser	missense	Exon 22 of 22	NP_001307676.1	K7EKI0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EVPL	ENST00000301607.8	TSL:1 MANE Select	c.6019G>A	p.Gly2007Ser	missense	Exon 22 of 22	ENSP00000301607.3	Q92817
EVPL	ENST00000586740.1	TSL:1	c.6085G>A	p.Gly2029Ser	missense	Exon 22 of 22	ENSP00000465630.1	K7EKI0
EVPL	ENST00000870829.1		c.5959G>A	p.Gly1987Ser	missense	Exon 22 of 22	ENSP00000540888.1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000533

AC:

AN:

187444

AF XY:

0.0000100

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000788

AC:

108

AN:

1369912

Hom.:

Cov.:

AF XY:

0.0000864

AC XY:

AN XY:

671492

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30506

American (AMR)

AF:

0.00

AC:

AN:

30786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20540

East Asian (EAS)

AF:

0.00

AC:

AN:

38772

South Asian (SAS)

AF:

0.0000137

AC:

AN:

72954

European-Finnish (FIN)

AF:

0.0000604

AC:

AN:

49646

Middle Eastern (MID)

AF:

0.000188

AC:

AN:

5328

European-Non Finnish (NFE)

AF:

0.0000958

AC:

102

AN:

1065122

Other (OTH)

AF:

0.00

AC:

AN:

56258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74386

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000482

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000386134), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Benign

0.088

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.052

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

PhyloP100

4.0

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.26

Sift

Benign

0.081

Sift4G

Uncertain

0.040

Polyphen

0.51

Vest4

0.19

MVP

0.73

MPC

0.74

ClinPred

0.98

GERP RS

4.5

PromoterAI

-0.043

Neutral

(source)

Varity_R

0.59

gMVP

0.80

Mutation Taster

=76/24

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over