rs555499592

Variant names:

• chr17-41757479-C-T
• rs555499592
• NM_002230.4:c.1982G>A
• JUP p.Arg661Gln

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_002230.4(JUP):​c.1982G>A​(p.Arg661Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,194 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R661W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 3.10
• 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: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08642942).
• BP6: Variant 17-41757479-C-T is Benign according to our data. Variant chr17-41757479-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409985.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000788 (12/152302) while in subpopulation EAS AF = 0.00135 (7/5180). AF 95% confidence interval is 0.000634. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1982G>A	p.Arg661Gln	missense	Exon 12 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1982G>A	p.Arg661Gln	missense	Exon 12 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1982G>A	p.Arg661Gln	missense	Exon 12 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.1982G>A	p.Arg661Gln	missense	Exon 12 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1982G>A	p.Arg661Gln	missense	Exon 12 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1982G>A	p.Arg661Gln	missense	Exon 12 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

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: 0.000139 AC: 35 AN: 251490 AF XY: 0.000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461892 Hom.: 0 Cov.: 38 AF XY: 0.0000536 AC XY: 39 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00103 AC: 41 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15300

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Arrhythmogenic right ventricular dysplasia 12 (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
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Benign	0.069	T
Sift4G	Benign	0.086	T
Varity_R		0.36
gMVP		0.64
Mutation Taster		=85/15	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs555499592;

hg19: chr17-39913731;

COSMIC: COSV60276975;

COSMIC: COSV60276975;