rs8067890

Variant names:

• chr17-41757818-G-T
• rs8067890
• NM_002230.4:c.1774-34C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002230.4(JUP):​c.1774-34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,578,612 control chromosomes in the GnomAD database, including 418,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.71 (38262 hom., cov: 31)
  • Exomes 𝑓: 0.73 (379975 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.546
• Publications: 13 publications found

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]

JUP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited epidermolysis bullosa

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Naxos disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-41757818-G-T is Benign according to our data. Variant chr17-41757818-G-T is described in ClinVar as Benign. ClinVar VariationId is 261474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.1774-34C>A		intron	N/A	NP_002221.1
	JUP	NM_001352773.2		c.1774-34C>A		intron	N/A	NP_001339702.1
	JUP	NM_001352774.2		c.1774-34C>A		intron	N/A	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.1774-34C>A		intron	N/A	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.1774-34C>A		intron	N/A	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.1774-34C>A		intron	N/A	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107125 AN: 151474 Hom.: 38238 Cov.: 31

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.699

GnomAD2 exomes AF: 0.665 AC: 146567 AN: 220376 AF XY: 0.677

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.726 AC: 1036468 AN: 1427020 Hom.: 379975 Cov.: 31 AF XY: 0.727 AC XY: 513371 AN XY: 706286

African (AFR) AF: 0.705 AC: 23154 AN: 32838

American (AMR) AF: 0.483 AC: 20411 AN: 42262

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 16799 AN: 23970

East Asian (EAS) AF: 0.470 AC: 18496 AN: 39372

South Asian (SAS) AF: 0.705 AC: 56700 AN: 80482

European-Finnish (FIN) AF: 0.697 AC: 36134 AN: 51820

Middle Eastern (MID) AF: 0.709 AC: 3147 AN: 4438

European-Non Finnish (NFE) AF: 0.750 AC: 819749 AN: 1092932

Other (OTH) AF: 0.711 AC: 41878 AN: 58906

GnomAD4 genome AF: 0.707 AC: 107187 AN: 151592 Hom.: 38262 Cov.: 31 AF XY: 0.702 AC XY: 52004 AN XY: 74052

African (AFR) AF: 0.711 AC: 29360 AN: 41300

American (AMR) AF: 0.605 AC: 9227 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2388 AN: 3462

East Asian (EAS) AF: 0.459 AC: 2366 AN: 5150

South Asian (SAS) AF: 0.691 AC: 3315 AN: 4798

European-Finnish (FIN) AF: 0.689 AC: 7245 AN: 10514

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50862 AN: 67822

Other (OTH) AF: 0.697 AC: 1466 AN: 2102

Alfa AF: 0.726 Hom.: 8242

Bravo AF: 0.697

Asia WGS AF: 0.560 AC: 1948 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Naxos disease Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Arrhythmogenic right ventricular dysplasia 12 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.25
DANN	Benign	0.59
PhyloP100		-0.55
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs8067890; hg19: chr17-39914070;