rs138366708

Variant names:

• chr17-41756202-T-C
• rs138366708
• NM_002230.4:c.2059A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002230.4(JUP):​c.2059A>G​(p.Ile687Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,613,902 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I687T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00070 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.38
• Publications: 1 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 cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• 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 (MetaRNN=0.010027677).
• BP6: Variant 17-41756202-T-C is Benign according to our data. Variant chr17-41756202-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000696 (106/152216) while in subpopulation AFR AF = 0.00253 (105/41516). AF 95% confidence interval is 0.00214. There are 2 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.2059A>G	p.Ile687Val	missense	Exon 13 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.2059A>G	p.Ile687Val	missense	Exon 13 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.2059A>G	p.Ile687Val	missense	Exon 13 of 15	NP_001339703.1	P14923

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.2059A>G	p.Ile687Val	missense	Exon 13 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.2059A>G	p.Ile687Val	missense	Exon 13 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.2059A>G	p.Ile687Val	missense	Exon 13 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152098 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 250970 AF XY: 0.000147

Gnomad AFR exome AF: 0.00315

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000125 AC: 182 AN: 1461686 Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 87 AN XY: 727126

African (AFR) AF: 0.00376 AC: 126 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111948

Other (OTH) AF: 0.000348 AC: 21 AN: 60386

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152216 Hom.: 2 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74426

African (AFR) AF: 0.00253 AC: 105 AN: 41516

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000313 Hom.: 0

Bravo AF: 0.000759

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (2)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (1)
-	-	1	JUP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		2.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.24	N
REVEL	Benign	0.046
Sift	Benign	0.42	T
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.29
MVP		0.65
MPC		0.40
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.089
gMVP		0.38
Mutation Taster		=99/1	polymorphism

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: rs138366708; hg19: chr17-39912454;