17-41754838-T-G

Variant names:

• chr17-41754838-T-G
• rs569644513
• NM_002230.4:c.*906A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002230.4(JUP):​c.*906A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000988 in 151,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JUP NM_002230.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.373
• 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 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000988 (15/151750) while in subpopulation SAS AF = 0.00147 (7/4768). AF 95% confidence interval is 0.000688. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*906A>C		3_prime_UTR	Exon 14 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.*906A>C		3_prime_UTR	Exon 14 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.*609A>C		3_prime_UTR	Exon 15 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.*906A>C		3_prime_UTR	Exon 14 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.*609A>C		3_prime_UTR	Exon 15 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.*609A>C		3_prime_UTR	Exon 15 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 15 AN: 151632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1604 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 876

African (AFR) AF: 0.00 AC: 0 AN: 60

American (AMR) AF: 0.00 AC: 0 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 48

East Asian (EAS) AF: 0.00 AC: 0 AN: 52

South Asian (SAS) AF: 0.00 AC: 0 AN: 18

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 862

Other (OTH) AF: 0.00 AC: 0 AN: 82

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151750 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74142

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.000131 AC: 2 AN: 15248

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00147 AC: 7 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67896

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000125

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 12 (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	-0.81
CADD	Benign	3.7
DANN	Benign	0.72
PhyloP100		-0.37
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: rs569644513; hg19: chr17-39911090;