rs782449369

Positions:

• chr17-41758746-T-A
• chr17-41758746-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_002230.4(JUP):​c.1622A>T​(p.His541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,454,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.03

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.1622A>T	p.His541Leu	missense_variant	9/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1622A>T	p.His541Leu	missense_variant	9/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9	c.1622A>T	p.His541Leu	missense_variant	9/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5	c.1622A>T	p.His541Leu	missense_variant	9/15	5		ENSP00000377507	P1
JUP	ENST00000585793.1	n.220A>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000427 AC: 1 AN: 234452 Hom.: 0 AF XY: 0.00000786 AC XY: 1 AN XY: 127238

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: 0.00

Gnomad NFE exome AF: 0.00000949

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1454212 Hom.: 0 Cov.: 32 AF XY: 0.0000125 AC XY: 9 AN XY: 722870

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: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary familial dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 31, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The p.H541L variant (also known as c.1622A>T), located in coding exon 8 of the JUP gene, results from an A to T substitution at nucleotide position 1622. The histidine at codon 541 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 520526). This variant has not been reported in the literature in individuals affected with JUP-related conditions. This variant is present in population databases (rs782449369, gnomAD 0.001%). This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 541 of the JUP protein (p.His541Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		0.38	B;B;B
Vest4		0.58
MutPred		0.45		Loss of disorder (P = 0.0322);Loss of disorder (P = 0.0322);Loss of disorder (P = 0.0322);
MVP		0.57
MPC		0.73
ClinPred		0.60	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.63

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: rs782449369; hg19: chr17-39914998;