rs727504778

Variant names:

• chr17-41757528-C-T
• rs727504778
• NM_002230.4:c.1933G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_Moderate BP6 BS1

The NM_002230.4(JUP):​c.1933G>A​(p.Ala645Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A645V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.57
• 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 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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885
• BP6: Variant 17-41757528-C-T is Benign according to our data. Variant chr17-41757528-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179306.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000274 (40/1461882) while in subpopulation SAS AF = 0.000255 (22/86258). AF 95% confidence interval is 0.000172. There are 1 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. This position passed quality control check.

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.1933G>A	p.Ala645Thr	missense	Exon 12 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1933G>A	p.Ala645Thr	missense	Exon 12 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1933G>A	p.Ala645Thr	missense	Exon 12 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.1933G>A	p.Ala645Thr	missense	Exon 12 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1933G>A	p.Ala645Thr	missense	Exon 12 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1933G>A	p.Ala645Thr	missense	Exon 12 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000278 AC: 7 AN: 251460 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461882 Hom.: 1 Cov.: 38 AF XY: 0.0000358 AC XY: 26 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112002

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (2)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.0084	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.73		Loss of catalytic residue at A645 (P = 0.0926)
MVP		0.88
MPC		0.64
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.79
Mutation Taster		=49/51	disease causing

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: rs727504778; hg19: chr17-39913780; COSMIC: COSV100159591; COSMIC: COSV100159591;