rs113994177

Variant names:

• chr17-41757421-CCA-C
• rs113994177
• NM_002230.4:c.2038_2039delTG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002230.4(JUP):​c.2038_2039delTG​(p.Trp680GlyfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: JUP NM_002230.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.06

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-41757421-CCA-C is Pathogenic according to our data. Variant chr17-41757421-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 13599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41757421-CCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.2038_2039delTG	p.Trp680GlyfsTer11	frameshift_variant	Exon 12 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.2038_2039delTG	p.Trp680GlyfsTer11	frameshift_variant	Exon 12 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.2038_2039delTG	p.Trp680GlyfsTer11	frameshift_variant	Exon 12 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.2038_2039delTG	p.Trp680GlyfsTer11	frameshift_variant	Exon 12 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Apr 08, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2038_2039delTG variant is expected to result in either an abnormal, truncated proteinproduct or loss of protein from this allele through nonsense-mediated mRNA decay. The c.2038_2039delTGvariant has been reported previously in multiple individuals with Naxos disease, an autosomal recessivedisorder identified in Naxos, Greece, and characterized by ARVC, palmoplantar keratoderma, and woolly hair(McKoy G et al., 2000; Antoniades L et al.., 2006; Lazaros G et al., 2009). These studies show that allindividuals who are homozygous for the c.2038_2039delTG (reported as 2157del2 due to alternatenomenclature) are affected with Naxos disease and all individuals who are heterozygous are unaffected(McKoy et al., 2000; Antoniades et al., 2006). In summary, c.2038_2039delTG in the JUP gene is interpreted as a pathogenic variant. -

Oct 08, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Naxos disease Pathogenic:1

Jun 17, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Pathogenic:1

Oct 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp680Glyfs*11) in the JUP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the JUP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with autosomal recessive Naxos disease (PMID: 10902626). It has also been observed to segregate with disease in related individuals. This variant is also known as 2157del2 or c.2157delTG-G680fsX690. ClinVar contains an entry for this variant (Variation ID: 13599). This variant disrupts a region of the JUP protein in which other variant(s) (p.Pro736Leu) have been observed in individuals with JUP-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Arrhythmogenic right ventricular dysplasia 12 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113994177; hg19: chr17-39913673;