chr17-76007209-C-G

Variant names:

• chr17-76007209-C-G
• rs577682130
• NM_001988.4:c.5996G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001988.4(EVPL):​c.5996G>C​(p.Arg1999Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R1999H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EVPL NM_001988.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009876698).

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.5996G>C	p.Arg1999Pro	missense	Exon 22 of 22	NP_001979.2	Q92817
	EVPL	NM_001320747.2		c.6062G>C	p.Arg2021Pro	missense	Exon 22 of 22	NP_001307676.1	K7EKI0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EVPL	ENST00000301607.8	TSL:1 MANE Select	c.5996G>C	p.Arg1999Pro	missense	Exon 22 of 22	ENSP00000301607.3	Q92817
	EVPL	ENST00000586740.1	TSL:1	c.6062G>C	p.Arg2021Pro	missense	Exon 22 of 22	ENSP00000465630.1	K7EKI0
	EVPL	ENST00000870829.1		c.5936G>C	p.Arg1979Pro	missense	Exon 22 of 22	ENSP00000540888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000289 AC: 59 AN: 204166 AF XY: 0.000155

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000861 AC: 12 AN: 1394508 Hom.: 0 Cov.: 30 AF XY: 0.00000873 AC XY: 6 AN XY: 686998

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

African (AFR) AF: 0.0000640 AC: 2 AN: 31272

American (AMR) AF: 0.00 AC: 0 AN: 34590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22130

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 77752

European-Finnish (FIN) AF: 0.000118 AC: 6 AN: 50748

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5452

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076296

Other (OTH) AF: 0.0000349 AC: 2 AN: 57288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.000759 AC: 92

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0099	T
MetaSVM	Uncertain	0.0013	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.8
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.60
Sift	Benign	0.038	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.77
MVP		0.88
MPC		0.85
ClinPred		0.11	T
GERP RS		5.5
PromoterAI		-0.0040	Neutral
Varity_R		0.93
gMVP		0.87

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

Other links and lift over

dbSNP: rs577682130; hg19: chr17-74003290;