NM_002230.4:c.1914C>G

Variant names:

• chr17-41757644-G-C
• rs368772249
• NM_002230.4:c.1914C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N638H) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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]

JUP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited epidermolysis bullosa

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Naxos disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.1914C>G	p.Asn638Lys	missense	Exon 11 of 14	NP_002221.1
	JUP	NM_001352773.2		c.1914C>G	p.Asn638Lys	missense	Exon 11 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.1914C>G	p.Asn638Lys	missense	Exon 11 of 15	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.1914C>G	p.Asn638Lys	missense	Exon 11 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.1914C>G	p.Asn638Lys	missense	Exon 11 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.1914C>G	p.Asn638Lys	missense	Exon 11 of 15	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 v4.9

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
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
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-1.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.57		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

Other links and lift over

dbSNP: rs368772249; hg19: chr17-39913896; COSMIC: COSV100159840; COSMIC: COSV100159840;