rs17850807

Variant names:

• chr17-41769481-G-A
• rs17850807
• NM_002230.4:c.405C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002230.4(JUP):​c.405C>T​(p.Asp135Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,613,032 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (237 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (214 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.14
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 17-41769481-G-A is Benign according to our data. Variant chr17-41769481-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.405C>T	p.Asp135Asp	synonymous	Exon 3 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.405C>T	p.Asp135Asp	synonymous	Exon 3 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.405C>T	p.Asp135Asp	synonymous	Exon 3 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.405C>T	p.Asp135Asp	synonymous	Exon 3 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.405C>T	p.Asp135Asp	synonymous	Exon 3 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.405C>T	p.Asp135Asp	synonymous	Exon 3 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.0310 AC: 4714 AN: 152172 Hom.: 237 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.00820 AC: 2027 AN: 247202 AF XY: 0.00603

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00314 AC: 4594 AN: 1460742 Hom.: 214 Cov.: 33 AF XY: 0.00261 AC XY: 1897 AN XY: 726620

African (AFR) AF: 0.107 AC: 3576 AN: 33468

American (AMR) AF: 0.00749 AC: 334 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5766

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1111688

Other (OTH) AF: 0.00701 AC: 423 AN: 60334

GnomAD4 genome AF: 0.0310 AC: 4717 AN: 152290 Hom.: 237 Cov.: 32 AF XY: 0.0298 AC XY: 2223 AN XY: 74478

African (AFR) AF: 0.106 AC: 4400 AN: 41536

American (AMR) AF: 0.0148 AC: 227 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68026

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0134 Hom.: 83

Bravo AF: 0.0355

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000654

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Naxos disease (1)
-	-	1	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.47
DANN	Benign	0.68
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs17850807; hg19: chr17-39925733;