rs75715269

Positions:

• chr17-41769255-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002230.4(JUP):​c.469-48C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,578,654 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (278 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (255 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0850

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-41769255-G-A is Benign according to our data. Variant chr17-41769255-G-A is described in ClinVar as [Benign]. Clinvar id is 261476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41769255-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.469-48C>T		intron_variant		ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.469-48C>T		intron_variant		1	NM_002230.4	ENSP00000377508.3

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5173 AN: 151998 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.00934 AC: 2190 AN: 234550 Hom.: 99 AF XY: 0.00709 AC XY: 912 AN XY: 128578

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00706

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000679

Gnomad OTH exome AF: 0.00353

GnomAD4 exome AF: 0.00398 AC: 5678 AN: 1426538 Hom.: 255 Cov.: 29 AF XY: 0.00338 AC XY: 2404 AN XY: 711292

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.00812

Gnomad4 ASJ exome AF: 0.000500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000794

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.00857

GnomAD4 genome AF: 0.0341 AC: 5194 AN: 152116 Hom.: 278 Cov.: 32 AF XY: 0.0331 AC XY: 2464 AN XY: 74392

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.0167

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0173 Hom.: 20

Bravo AF: 0.0390

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.30
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75715269; hg19: chr17-39925507;