17-76007119-G-C

Variant names:

• chr17-76007119-G-C
• rs375561600
• NM_001988.4:c.6086C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001988.4(EVPL):​c.6086C>G​(p.Pro2029Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,329,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P2029T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: EVPL NM_001988.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.68
• 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: 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=0.27085146).

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.6086C>G	p.Pro2029Arg	missense	Exon 22 of 22	NP_001979.2	Q92817
	EVPL	NM_001320747.2		c.6152C>G	p.Pro2051Arg	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.6086C>G	p.Pro2029Arg	missense	Exon 22 of 22	ENSP00000301607.3	Q92817
	EVPL	ENST00000586740.1	TSL:1	c.6152C>G	p.Pro2051Arg	missense	Exon 22 of 22	ENSP00000465630.1	K7EKI0
	EVPL	ENST00000870829.1		c.6026C>G	p.Pro2009Arg	missense	Exon 22 of 22	ENSP00000540888.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1329998 Hom.: 0 Cov.: 30 AF XY: 0.00000308 AC XY: 2 AN XY: 648546

African (AFR) AF: 0.00 AC: 0 AN: 29884

American (AMR) AF: 0.00 AC: 0 AN: 28052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19284

East Asian (EAS) AF: 0.00 AC: 0 AN: 38270

South Asian (SAS) AF: 0.00 AC: 0 AN: 64694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4890

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1048124

Other (OTH) AF: 0.00 AC: 0 AN: 54752

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.3
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.7
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.15
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.056	T
Polyphen		0.92	P
Vest4		0.25
MutPred		0.29		Gain of MoRF binding (P = 0.0106)
MVP		0.76
MPC		0.20
ClinPred		0.69	D
GERP RS		2.0
PromoterAI		0.028	Neutral
Varity_R		0.073
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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: rs375561600; hg19: chr17-74003200;