rs1205967739

Positions:

• chr17-41769507-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002230.4(JUP):​c.379A>G​(p.Ile127Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,460,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15517735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.379A>G	p.Ile127Val	missense_variant	3/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.379A>G	p.Ile127Val	missense_variant	3/14	1	NM_002230.4	ENSP00000377508	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246508 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133580

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1460522 Hom.: 0 Cov.: 34 AF XY: 0.00000964 AC XY: 7 AN XY: 726494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000565

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces isoleucine with valine at codon 127 of the JUP protein (p.Ile127Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with JUP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.34
DEOGEN2	Benign	0.17	T;T;T;.;T;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	.;.;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.93	L;L;L;.;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.33	N;N;N;N;N;N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;.;.;.;.
Polyphen		0.0	B;B;B;.;.;.;.
Vest4		0.28
MutPred		0.49		Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);Loss of ubiquitination at K124 (P = 0.1435);
MVP		0.40
MPC		0.073
ClinPred		0.16	T
GERP RS		5.5
Varity_R		0.48
gMVP		0.22

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: rs1205967739; hg19: chr17-39925759;