17-41769620-A-G

Variant names:

• chr17-41769620-A-G
• rs542745694
• NM_002230.4:c.266T>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS1

The NM_002230.4(JUP):​c.266T>C​(p.Met89Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 9.32

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 17-41769620-A-G is Benign according to our data. Variant chr17-41769620-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 583093.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000103 (15/1453648) while in subpopulation AMR AF= 0.000279 (12/42972). AF 95% confidence interval is 0.00016. There are 0 homozygotes in gnomad4_exome. There are 6 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.266T>C	p.Met89Thr	missense_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.266T>C	p.Met89Thr	missense_variant	Exon 3 of 14	1	NM_002230.4	ENSP00000377508.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000559 AC: 13 AN: 232480 Hom.: 0 AF XY: 0.0000239 AC XY: 3 AN XY: 125424

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000343

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1453648 Hom.: 0 Cov.: 34 AF XY: 0.00000831 AC XY: 6 AN XY: 722282

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000279

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Aug 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Apr 21, 2017

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

This patient has a diagnosis of HCM and had a Comprehensive Cardiomyopathy Panel with the GeneDx laboratory. The test included sequencing of 76 genes and additional deletion/duplication analysis of 60 of those genes (nuclear genes) associated with various forms of cardiomyopathy: ABCC9, ACTC (ACTC1), ACTN2, ANKRD1, BAG3 , BRAF, CAV3, CRYAB, CSRP3, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, FKTN, GATAD1, GLA, HRAS, ILK, JPH2, JUP, KRAS, LAMA4, LAMP2, LDB3 (ZASP), LMNA, MAP2K1, MAP2K2, MTND1, MTND5, MTND6, MTTD, MTTG, MTTH, MTTI, MTTK, MTTL1, MTTL2, MTTM, MTTQ, MTTS1, MTTS2, MYBPC3, MYH7, MYL2, MYL3, MYLK2, MYOZ2, MYPN, NEBL , NEXN, NRAS, PDLIM3, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, SOS1, TAZ, TCAP, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL. 7 variants were reported. We believe the MYH7 variant is the most likely to be pathogenic: • p.Ala868Pro (A868P; c.2602G>C) in the MYH7 gene • p.Leu327Val (L327V; c.979C>G) in the PRKAG2 gene • p.Pro323Thr (P323T; c.967C>A) in the GLA gene • p.Ala749Ile (A749I; c.2245_2246delGCinsAT) in the PKP2 gene • p.Met89Thr (M89T; c.266T>C) in the JUP gene • p.Asp2771Ala (D2771A; c.8312A>C) in the DMD gene • Duplication of at least exons 1-2 of the LAMA4 gene Given the large number of genes included on this panel, and the large and variable nature of some of these genes, it is expected that most individuals (including individuals who don't have inherited cardiac disease) would have at least one and possibly several rare variants found with this test. As a result, it is important to consider the data available on each variant to determine whether it is a disease-predisposing variant or one of the many benign rare variants that we all have in our DNA. p.Met89Thr (M89T; c.266T>C) in exon 3 of the JUP gene (NM_002230.2; ENST00000393931.7) Chromosome position: 17:39925872 A / G Based on the information reviewed below, including lack of case data, we classify it as a Variant of Uncertain Signficance (VUS), concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. Because of its increased prevalence among individuals with Latino ancestry (like our patient), we suspect that it is more likely to be benign. Of note, the JUP gene is associated with ARVC, which is not our patient’s phenotype. This variant has not been reported in the literature in association with disease. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Methionine with a polar Threonine. Methionine at this location is highly conserved across vertebrate species, although it is replaced by another nonpolar amino acid in a few species. There are no missense variants within 10 residues currently listed as Pathogenic or Likely Pathogenic in ClinVar, which suggests this region of the protein may be tolerant of change. This variant was reported in 12/113,726 individuals (MAF 0.005%) in the gnomAD database, which includes ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 10/15,634 Latino individuals (for the highest allele frequency: 0.032%), and 2/51,540 non-Finnish Europeans (MAF 0.002%). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. Of note, our patient’s ancestry is Latino. -

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 89 of the JUP protein (p.Met89Thr). This variant is present in population databases (rs542745694, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 583093). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Benign:1

Nov 05, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: JUP c.266T>C (p.Met89Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 232480 control chromosomes, predominantly at a frequency of 0.00034 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 34 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.266T>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiovascular phenotype Benign:1

Aug 12, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;D;.;T;.;T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	.;.;T;T;T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0040	D;D;D;.;.;.;.;D
Polyphen		1.0	D;D;D;.;.;.;.;.
Vest4		0.84
MutPred		0.67		Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);Gain of phosphorylation at M89 (P = 0.0273);
MVP		0.76
MPC		0.18
ClinPred		0.41	T
GERP RS		5.8
Varity_R		0.50
gMVP		0.90

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: rs542745694; hg19: chr17-39925872;