rs7405731

Variant names:

• chr17-41769673-A-G
• rs7405731
• NM_002230.4:c.213T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-41769673-A-G
• chr17-41769673-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002230.4(JUP):​c.213T>C​(p.Asp71Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 1,606,858 control chromosomes in the GnomAD database, including 458,367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (45851 hom., cov: 32)
  • Exomes 𝑓: 0.75 (412516 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.455

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-41769673-A-G is Benign according to our data. Variant chr17-41769673-A-G is described in ClinVar as [Benign]. Clinvar id is 45845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41769673-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.455 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.213T>C	p.Asp71Asp	synonymous_variant	Exon 3 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.213T>C	p.Asp71Asp	synonymous_variant	Exon 3 of 14	1	NM_002230.4	ENSP00000377508.3

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117207 AN: 152052 Hom.: 45801 Cov.: 32

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.809

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.670

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.763

Gnomad OTH AF: 0.763

GnomAD3 exomes AF: 0.711 AC: 167306 AN: 235266 Hom.: 60982 AF XY: 0.721 AC XY: 91753 AN XY: 127262

Gnomad AFR exome AF: 0.887

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.826

Gnomad EAS exome AF: 0.511

Gnomad SAS exome AF: 0.758

Gnomad FIN exome AF: 0.681

Gnomad NFE exome AF: 0.758

Gnomad OTH exome AF: 0.734

GnomAD4 exome AF: 0.750 AC: 1091432 AN: 1454688 Hom.: 412516 Cov.: 63 AF XY: 0.752 AC XY: 543348 AN XY: 722944

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.816

Gnomad4 EAS exome AF: 0.518

Gnomad4 SAS exome AF: 0.759

Gnomad4 FIN exome AF: 0.684

Gnomad4 NFE exome AF: 0.763

Gnomad4 OTH exome AF: 0.757

GnomAD4 genome AF: 0.771 AC: 117318 AN: 152170 Hom.: 45851 Cov.: 32 AF XY: 0.762 AC XY: 56711 AN XY: 74376

Gnomad4 AFR AF: 0.882

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.809

Gnomad4 EAS AF: 0.517

Gnomad4 SAS AF: 0.750

Gnomad4 FIN AF: 0.670

Gnomad4 NFE AF: 0.763

Gnomad4 OTH AF: 0.767

Alfa AF: 0.745 Hom.: 18294

Bravo AF: 0.770

Asia WGS AF: 0.673 AC: 2346 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 17, 2016

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 30, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Naxos disease Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Arrhythmogenic right ventricular dysplasia 12 Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 09, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.66
CADD	Benign	9.5
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7405731; hg19: chr17-39925925; COSMIC: COSV60277378; COSMIC: COSV60277378;