NM_002230.4:c.2178C>G

Variant names:

• chr17-41755804-G-C
• rs141295561
• NM_002230.4:c.2178C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002230.4(JUP):​c.2178C>G​(p.Ile726Met) 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 benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I726I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.94
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022228867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.2178C>G	p.Ile726Met	missense_variant	Exon 14 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.2178C>G	p.Ile726Met	missense_variant	Exon 14 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.2178C>G	p.Ile726Met	missense_variant	Exon 14 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.2178C>G	p.Ile726Met	missense_variant	Exon 14 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.026
DANN	Benign	0.48
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.21	.;.;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.41	N;N;N
PhyloP100		-3.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.41	N;N;N
REVEL	Benign	0.051
Sift	Benign	0.84	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.090
MutPred		0.20		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.32
MPC		0.49
ClinPred		0.026	T
GERP RS		-9.2
Varity_R		0.025
gMVP		0.43

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: rs141295561; hg19: chr17-39912056;