rs782547688

Variant names:

• chr17-41757682-C-A
• rs782547688
• NM_002230.4:c.1876G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41757682-C-A
• chr17-41757682-C-G
• chr17-41757682-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002230.4(JUP):​c.1876G>T​(p.Ala626Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A626T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

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.1876G>T	p.Ala626Ser	missense	Exon 11 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1876G>T	p.Ala626Ser	missense	Exon 11 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1876G>T	p.Ala626Ser	missense	Exon 11 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.1876G>T	p.Ala626Ser	missense	Exon 11 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1876G>T	p.Ala626Ser	missense	Exon 11 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1876G>T	p.Ala626Ser	missense	Exon 11 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248994 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 38 AF XY: 0.00000138 AC XY: 1 AN XY: 726894

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111702

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.018	D
Polyphen		0.68	P
Vest4		0.77
MutPred		0.60		Gain of glycosylation at A626 (P = 0.0192)
MVP		0.80
MPC		1.1
ClinPred		0.77	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.54
gMVP		0.57

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: rs782547688; hg19: chr17-39913934;