17-41769461-C-T

Variant names:

• chr17-41769461-C-T
• rs41283425
• NM_002230.4:c.425G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002230.4(JUP):​c.425G>A​(p.Arg142His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,612,690 control chromosomes in the GnomAD database, including 2,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R142C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.039 (128 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2047 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 7.90
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00889793).
• BP6: Variant 17-41769461-C-T is Benign according to our data. Variant chr17-41769461-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

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.425G>A	p.Arg142His	missense	Exon 3 of 14	NP_002221.1
	JUP	NM_001352773.2		c.425G>A	p.Arg142His	missense	Exon 3 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.425G>A	p.Arg142His	missense	Exon 3 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.425G>A	p.Arg142His	missense	Exon 3 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.425G>A	p.Arg142His	missense	Exon 3 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.425G>A	p.Arg142His	missense	Exon 3 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5973 AN: 152102 Hom.: 130 Cov.: 32

Gnomad AFR AF: 0.00797

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0332

Gnomad FIN AF: 0.0558

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0437 AC: 10768 AN: 246352 AF XY: 0.0469

Gnomad AFR exome AF: 0.00754

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0662

Gnomad EAS exome AF: 0.000385

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.0563

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0497 AC: 72625 AN: 1460470 Hom.: 2047 Cov.: 33 AF XY: 0.0503 AC XY: 36564 AN XY: 726432

African (AFR) AF: 0.00777 AC: 260 AN: 33470

American (AMR) AF: 0.0277 AC: 1236 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0639 AC: 1666 AN: 26078

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39688

South Asian (SAS) AF: 0.0452 AC: 3886 AN: 85980

European-Finnish (FIN) AF: 0.0598 AC: 3171 AN: 53068

Middle Eastern (MID) AF: 0.0974 AC: 561 AN: 5760

European-Non Finnish (NFE) AF: 0.0529 AC: 58779 AN: 1111516

Other (OTH) AF: 0.0506 AC: 3053 AN: 60322

GnomAD4 genome AF: 0.0392 AC: 5966 AN: 152220 Hom.: 128 Cov.: 32 AF XY: 0.0383 AC XY: 2854 AN XY: 74434

African (AFR) AF: 0.00794 AC: 330 AN: 41538

American (AMR) AF: 0.0341 AC: 521 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 232 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0326 AC: 157 AN: 4820

European-Finnish (FIN) AF: 0.0558 AC: 592 AN: 10608

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0589 AC: 4006 AN: 67996

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0526 Hom.: 811

Bravo AF: 0.0369

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0581 AC: 500

ExAC AF: 0.0440 AC: 5347

Asia WGS AF: 0.0170 AC: 59 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Arrhythmogenic right ventricular dysplasia 12 (2)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (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	Uncertain	0.56
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.26
MPC		0.46
ClinPred		0.014	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.59
gMVP		0.53
Mutation Taster		=96/4	polymorphism (auto)

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: rs41283425; hg19: chr17-39925713;