rs8067890

Positions:

• chr17-41757818-G-T

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.1774-34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,578,612 control chromosomes in the GnomAD database, including 418,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.71 (38262 hom., cov: 31)
  • Exomes 𝑓: 0.73 (379975 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.546

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: This place is a probable branch point but likely benign (scored 0 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-41757818-G-T is Benign according to our data. Variant chr17-41757818-G-T is described in ClinVar as [Benign]. Clinvar id is 261474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41757818-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.1774-34C>A		intron_variant		ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1774-34C>A		intron_variant		1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9	c.1774-34C>A		intron_variant		1		ENSP00000311113	P1
JUP	ENST00000393930.5	c.1774-34C>A		intron_variant		5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes AF: 0.707 AC: 107125 AN: 151474 Hom.: 38238 Cov.: 31

Gnomad AFR AF: 0.711

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.460

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.699

GnomAD3 exomes AF: 0.665 AC: 146567 AN: 220376 Hom.: 50020 AF XY: 0.677 AC XY: 80479 AN XY: 118902

Gnomad AFR exome AF: 0.711

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.704

Gnomad EAS exome AF: 0.460

Gnomad SAS exome AF: 0.705

Gnomad FIN exome AF: 0.693

Gnomad NFE exome AF: 0.741

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.726 AC: 1036468 AN: 1427020 Hom.: 379975 Cov.: 31 AF XY: 0.727 AC XY: 513371 AN XY: 706286

Gnomad4 AFR exome AF: 0.705

Gnomad4 AMR exome AF: 0.483

Gnomad4 ASJ exome AF: 0.701

Gnomad4 EAS exome AF: 0.470

Gnomad4 SAS exome AF: 0.705

Gnomad4 FIN exome AF: 0.697

Gnomad4 NFE exome AF: 0.750

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.707 AC: 107187 AN: 151592 Hom.: 38262 Cov.: 31 AF XY: 0.702 AC XY: 52004 AN XY: 74052

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.459

Gnomad4 SAS AF: 0.691

Gnomad4 FIN AF: 0.689

Gnomad4 NFE AF: 0.750

Gnomad4 OTH AF: 0.697

Alfa AF: 0.726 Hom.: 8242

Bravo AF: 0.697

Asia WGS AF: 0.560 AC: 1948 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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

-

- -

Naxos disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Arrhythmogenic right ventricular dysplasia 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.25
DANN	Benign	0.59
BranchPoint Hunter		0.0

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: rs8067890; hg19: chr17-39914070;