rs143043662

Variant names:

• chr17-41757519-C-T
• rs143043662
• NM_002230.4:c.1942G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002230.4(JUP):​c.1942G>A​(p.Val648Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,614,148 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V648V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: 7.63
• Publications: 25 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012058109).
• BP6: Variant 17-41757519-C-T is Benign according to our data. Variant chr17-41757519-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45842.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00723 (1101/152270) while in subpopulation NFE AF = 0.0121 (822/68008). AF 95% confidence interval is 0.0114. There are 4 homozygotes in GnomAd4. There are 518 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.1942G>A	p.Val648Ile	missense	Exon 12 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1942G>A	p.Val648Ile	missense	Exon 12 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1942G>A	p.Val648Ile	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.1942G>A	p.Val648Ile	missense	Exon 12 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1942G>A	p.Val648Ile	missense	Exon 12 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1942G>A	p.Val648Ile	missense	Exon 12 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1101 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00719 AC: 1807 AN: 251466 AF XY: 0.00703

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.0109 AC: 16002 AN: 1461878 Hom.: 109 Cov.: 38 AF XY: 0.0106 AC XY: 7688 AN XY: 727244

African (AFR) AF: 0.00173 AC: 58 AN: 33480

American (AMR) AF: 0.00188 AC: 84 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86258

European-Finnish (FIN) AF: 0.0141 AC: 753 AN: 53420

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14444 AN: 1111996

Other (OTH) AF: 0.00919 AC: 555 AN: 60396

GnomAD4 genome AF: 0.00723 AC: 1101 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74450

African (AFR) AF: 0.00243 AC: 101 AN: 41552

American (AMR) AF: 0.00216 AC: 33 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0125 AC: 133 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0121 AC: 822 AN: 68008

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00941 Hom.: 23

Bravo AF: 0.00629

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00743 AC: 902

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	6	not provided (6)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy;C0878544:Cardiomyopathy (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	Benign	0.28
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.27	T
Polyphen		0.42	B
Vest4		0.66
MVP		0.62
MPC		0.53
ClinPred		0.012	T
GERP RS		5.0
Varity_R		0.27
gMVP		0.50
Mutation Taster		=69/31	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: rs143043662; hg19: chr17-39913771; COSMIC: COSV106099575; COSMIC: COSV106099575;