NM_002230.4:c.*670G>C

Variant names:

• chr17-41755074-C-G
• rs782166986
• NM_002230.4:c.*670G>C

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.*670G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 235,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: JUP NM_002230.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.38
• 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 cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• 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 (BayesDel_noAF=-0.87).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.*670G>C		3_prime_UTR	Exon 14 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.*670G>C		3_prime_UTR	Exon 14 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.*373G>C		3_prime_UTR	Exon 15 of 15	NP_001339703.1	P14923

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.*670G>C		3_prime_UTR	Exon 14 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.*373G>C		3_prime_UTR	Exon 15 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.*373G>C		3_prime_UTR	Exon 15 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000424 AC: 1 AN: 235872 Hom.: 0 Cov.: 0 AF XY: 0.00000836 AC XY: 1 AN XY: 119644

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6970

American (AMR) AF: 0.00 AC: 0 AN: 7056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8936

East Asian (EAS) AF: 0.00 AC: 0 AN: 22144

South Asian (SAS) AF: 0.00 AC: 0 AN: 2080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1236

European-Non Finnish (NFE) AF: 0.00000659 AC: 1 AN: 151744

Other (OTH) AF: 0.00 AC: 0 AN: 15736

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.050
DANN	Benign	0.36
PhyloP100		-3.4

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: rs782166986; hg19: chr17-39911326;