rs75715269

Variant names:

• chr17-41769255-G-A
• rs75715269
• NM_002230.4:c.469-48C>T

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.469-48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,578,654 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (255 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0850
• Publications: 2 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: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-41769255-G-A is Benign according to our data. Variant chr17-41769255-G-A is described in ClinVar as [Benign]. Clinvar id is 261476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.469-48C>T		intron_variant	Intron 3 of 13	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.469-48C>T		intron_variant	Intron 3 of 13	1	NM_002230.4	ENSP00000377508.3

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5173 AN: 151998 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.00934 AC: 2190 AN: 234550 AF XY: 0.00709

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00706

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.00353

GnomAD4 exome AF: 0.00398 AC: 5678 AN: 1426538 Hom.: 255 Cov.: 29 AF XY: 0.00338 AC XY: 2404 AN XY: 711292

African (AFR) AF: 0.117 AC: 3853 AN: 33016

American (AMR) AF: 0.00812 AC: 363 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000500 AC: 13 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.000794 AC: 68 AN: 85680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39306

Middle Eastern (MID) AF: 0.00381 AC: 17 AN: 4464

European-Non Finnish (NFE) AF: 0.000780 AC: 854 AN: 1094240

Other (OTH) AF: 0.00857 AC: 510 AN: 59516

GnomAD4 genome AF: 0.0341 AC: 5194 AN: 152116 Hom.: 278 Cov.: 32 AF XY: 0.0331 AC XY: 2464 AN XY: 74392

African (AFR) AF: 0.116 AC: 4810 AN: 41458

American (AMR) AF: 0.0167 AC: 256 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 67986

Other (OTH) AF: 0.0246 AC: 52 AN: 2110

Alfa AF: 0.0157 Hom.: 34

Bravo AF: 0.0390

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.68
PhyloP100		-0.085
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75715269; hg19: chr17-39925507;