17-41755458-G-A

Position:

• chr17-41755458-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.*286C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 427,580 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (247 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (50 hom.)
• Consequence: JUP NM_002230.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.630

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=-0.84).
• BP6: Variant 17-41755458-G-A is Benign according to our data. Variant chr17-41755458-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 323157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.*286C>T		3_prime_UTR_variant	14/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.*286C>T		3_prime_UTR_variant	14/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9	c.*15-26C>T		intron_variant		1		ENSP00000311113	P1
JUP	ENST00000393930.5	c.*15-26C>T		intron_variant		5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes AF: 0.0306 AC: 4645 AN: 151968 Hom.: 246 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0201

GnomAD4 exome AF: 0.00415 AC: 1143 AN: 275494 Hom.: 50 Cov.: 0 AF XY: 0.00356 AC XY: 500 AN XY: 140274

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.00946

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000265

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000183

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0306 AC: 4655 AN: 152086 Hom.: 247 Cov.: 32 AF XY: 0.0292 AC XY: 2168 AN XY: 74362

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0177 Hom.: 16

Bravo AF: 0.0349

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Naxos disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Arrhythmogenic right ventricular dysplasia 12 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.69
BranchPoint Hunter		0.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs73983656; hg19: chr17-39911710;