rs34890640

Variant names:

• chr17-41767511-G-A
• rs34890640
• NM_002230.4:c.777C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002230.4(JUP):​c.777C>T​(p.Gly259Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,609,316 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (12 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -2.16
• 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 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, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-41767511-G-A is Benign according to our data. Variant chr17-41767511-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45857.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00462 (702/151918) while in subpopulation AFR AF = 0.0167 (692/41450). AF 95% confidence interval is 0.0157. There are 11 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 14	NP_002221.1
	JUP	NM_001352773.2		c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 15	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.777C>T	p.Gly259Gly	synonymous	Exon 5 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 702 AN: 151802 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.00144

GnomAD2 exomes AF: 0.00118 AC: 296 AN: 251310 AF XY: 0.000729

Gnomad AFR exome AF: 0.0170

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000499 AC: 727 AN: 1457398 Hom.: 12 Cov.: 46 AF XY: 0.000465 AC XY: 337 AN XY: 725064

African (AFR) AF: 0.0184 AC: 613 AN: 33362

American (AMR) AF: 0.000314 AC: 14 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86240

European-Finnish (FIN) AF: 0.000153 AC: 8 AN: 52182

Middle Eastern (MID) AF: 0.00192 AC: 11 AN: 5744

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1109748

Other (OTH) AF: 0.000883 AC: 53 AN: 60048

GnomAD4 genome AF: 0.00462 AC: 702 AN: 151918 Hom.: 11 Cov.: 31 AF XY: 0.00447 AC XY: 332 AN XY: 74292

African (AFR) AF: 0.0167 AC: 692 AN: 41450

American (AMR) AF: 0.000458 AC: 7 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10502

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00237 Hom.: 1

Bravo AF: 0.00530

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	JUP-related disorder (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	-0.65
CADD	Benign	6.1
DANN	Benign	0.83
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs34890640; hg19: chr17-39923763; COSMIC: COSV60277592; COSMIC: COSV60277592;