chr17-41767362-A-G

Variant names:

• chr17-41767362-A-G
• rs12942034
• NM_002230.4:c.909+17T>C

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.909+17T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 1,611,860 control chromosomes in the GnomAD database, including 522,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50207 hom., cov: 32)
  • Exomes 𝑓: 0.80 (472130 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.00800
• Publications: 9 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 (BayesDel_noAF=-0.96).
• BP6: Variant 17-41767362-A-G is Benign according to our data. Variant chr17-41767362-A-G is described in ClinVar as Benign. ClinVar VariationId is 258593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.879 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.909+17T>C		intron	N/A	NP_002221.1
	JUP	NM_001352773.2		c.909+17T>C		intron	N/A	NP_001339702.1
	JUP	NM_001352774.2		c.909+17T>C		intron	N/A	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.909+17T>C		intron	N/A	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.909+17T>C		intron	N/A	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.909+17T>C		intron	N/A	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122885 AN: 152080 Hom.: 50160 Cov.: 32

Gnomad AFR AF: 0.886

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.789

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.798

GnomAD2 exomes AF: 0.751 AC: 188199 AN: 250442 AF XY: 0.763

Gnomad AFR exome AF: 0.892

Gnomad AMR exome AF: 0.531

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.501

Gnomad FIN exome AF: 0.787

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.768

GnomAD4 exome AF: 0.801 AC: 1169037 AN: 1459662 Hom.: 472130 Cov.: 36 AF XY: 0.802 AC XY: 582409 AN XY: 726206

African (AFR) AF: 0.890 AC: 29764 AN: 33440

American (AMR) AF: 0.548 AC: 24500 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 20829 AN: 26120

East Asian (EAS) AF: 0.509 AC: 20216 AN: 39688

South Asian (SAS) AF: 0.800 AC: 68945 AN: 86206

European-Finnish (FIN) AF: 0.788 AC: 41812 AN: 53080

Middle Eastern (MID) AF: 0.809 AC: 4586 AN: 5668

European-Non Finnish (NFE) AF: 0.820 AC: 910565 AN: 1110484

Other (OTH) AF: 0.793 AC: 47820 AN: 60294

GnomAD4 genome AF: 0.808 AC: 122992 AN: 152198 Hom.: 50207 Cov.: 32 AF XY: 0.801 AC XY: 59600 AN XY: 74392

African (AFR) AF: 0.886 AC: 36833 AN: 41560

American (AMR) AF: 0.677 AC: 10352 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.789 AC: 2738 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2629 AN: 5156

South Asian (SAS) AF: 0.792 AC: 3818 AN: 4822

European-Finnish (FIN) AF: 0.785 AC: 8304 AN: 10580

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55659 AN: 68010

Other (OTH) AF: 0.798 AC: 1688 AN: 2114

Alfa AF: 0.815 Hom.: 9313

Bravo AF: 0.798

Asia WGS AF: 0.683 AC: 2379 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Naxos disease (1)
-	-	1	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.74
PhyloP100		-0.0080
Mutation Taster		=100/0	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: rs12942034; hg19: chr17-39923614; COSMIC: COSV60277010; COSMIC: COSV60277010;