17-76007120-G-T

Variant names:

• chr17-76007120-G-T
• NM_001988.4:c.6085C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001988.4(EVPL):​c.6085C>A​(p.Pro2029Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000225 in 1,333,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: EVPL NM_001988.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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]

ACMG classification

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=0.15039748).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EVPL	NM_001988.4	c.6085C>A	p.Pro2029Thr	missense_variant	Exon 22 of 22	ENST00000301607.8	NP_001979.2
EVPL	NM_001320747.2	c.6151C>A	p.Pro2051Thr	missense_variant	Exon 22 of 22		NP_001307676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EVPL	ENST00000301607.8	c.6085C>A	p.Pro2029Thr	missense_variant	Exon 22 of 22	1	NM_001988.4	ENSP00000301607.3
EVPL	ENST00000586740.1	c.6151C>A	p.Pro2051Thr	missense_variant	Exon 22 of 22	1		ENSP00000465630.1
EVPL	ENST00000589231.1	c.322C>A	p.Pro108Thr	missense_variant	Exon 1 of 2	3		ENSP00000467717.1
EVPL	ENST00000587569.5	n.6554C>A		non_coding_transcript_exon_variant	Exon 20 of 20	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000225 AC: 3 AN: 1333150 Hom.: 0 Cov.: 30 AF XY: 0.00000154 AC XY: 1 AN XY: 650238

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: 0.00000286

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6085C>A (p.P2029T) alteration is located in exon 22 (coding exon 22) of the EVPL gene. This alteration results from a C to A substitution at nucleotide position 6085, causing the proline (P) at amino acid position 2029 to be replaced by a threonine (T). 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	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	6.6
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.7	.;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	.;N;.
REVEL	Benign	0.037
Sift	Benign	0.084	.;T;.
Sift4G	Benign	0.16	T;T;T
Polyphen		0.38	.;B;.
Vest4		0.14, 0.11
MutPred		0.18		.;Gain of phosphorylation at P2029 (P = 0.0288);.;
MVP		0.76
MPC		0.21
ClinPred		0.17	T
GERP RS		3.4
Varity_R		0.048
gMVP		0.33

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.

Other links and lift over

hg19: chr17-74003201;