rs12942034

Positions:

• chr17-41767362-A-G
• chr17-41767362-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002230.4(JUP):​c.909+17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,611,860 control chromosomes in the GnomAD database, including 522,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50207 hom., cov: 32)
  • Exomes 𝑓: 0.80 (472130 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.00800

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-41767362-A-G is Benign according to our data. Variant chr17-41767362-A-G is described in ClinVar as [Benign]. Clinvar id is 258593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41767362-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4	c.909+17T>C		intron_variant		ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.909+17T>C		intron_variant		1	NM_002230.4	P1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122885 AN: 152080 Hom.: 50160 Cov.: 32

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.798

GnomAD3 exomes AF: 0.751 AC: 188199 AN: 250442 Hom.: 72781 AF XY: 0.763 AC XY: 103377 AN XY: 135472

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.501

Gnomad SAS exome AF: 0.799

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.801 AC: 1169037 AN: 1459662 Hom.: 472130 Cov.: 36 AF XY: 0.802 AC XY: 582409 AN XY: 726206

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.797

Gnomad4 EAS exome AF: 0.509

Gnomad4 SAS exome AF: 0.800

Gnomad4 FIN exome AF: 0.788

Gnomad4 NFE exome AF: 0.820

Gnomad4 OTH exome AF: 0.793

GnomAD4 genome AF: 0.808 AC: 122992 AN: 152198 Hom.: 50207 Cov.: 32 AF XY: 0.801 AC XY: 59600 AN XY: 74392

Gnomad4 AFR AF: 0.886

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.789

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.792

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.818

Gnomad4 OTH AF: 0.798

Alfa AF: 0.815 Hom.: 9313

Bravo AF: 0.798

Asia WGS AF: 0.683 AC: 2379 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Naxos disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Arrhythmogenic right ventricular dysplasia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.74

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

LitVar

Other links and lift over

dbSNP: rs12942034; hg19: chr17-39923614; COSMIC: COSV60277010; COSMIC: COSV60277010;