17-41757644-G-C

Variant names:

• chr17-41757644-G-C
• NM_002230.4:c.1914C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002230.4(JUP):​c.1914C>G​(p.Asn638Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.1914C>G	p.Asn638Lys	missense_variant	Exon 11 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1914C>G	p.Asn638Lys	missense_variant	Exon 11 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.1914C>G	p.Asn638Lys	missense_variant	Exon 11 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.1914C>G	p.Asn638Lys	missense_variant	Exon 11 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

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

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 638 of the JUP protein (p.Asn638Lys). This variant is not present in population databases (gnomAD 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.8
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D;D
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.50	N
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.82
MutPred		0.57		Gain of ubiquitination at N638 (P = 0.0066);Gain of ubiquitination at N638 (P = 0.0066);Gain of ubiquitination at N638 (P = 0.0066);
MVP		0.62
MPC		1.5
ClinPred		1.0	D
GERP RS		-8.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39913896; COSMIC: COSV100159840; COSMIC: COSV100159840;