chr17-41769119-A-ACCAGCTGGGGCGAGC

Variant names:

• chr17-41769119-A-ACCAGCTGGGGCGAGC
• rs1555605296
• NM_002230.4:c.542_556dupGCTCGCCCCAGCTGG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM4 PP3

The NM_002230.4(JUP):​c.542_556dupGCTCGCCCCAGCTGG​(p.Gly181_Leu185dup) variant causes a conservative inframe insertion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: JUP NM_002230.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.89
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002230.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 14	NP_002221.1
	JUP	NM_001352773.2		c.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 15	NP_001339703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.542_556dupGCTCGCCCCAGCTGG	p.Gly181_Leu185dup	conservative_inframe_insertion	Exon 4 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 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: 0.00

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

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=52/48	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555605296; hg19: chr17-39925371;