NM_002230.4:c.1281G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1

The NM_002230.4(JUP):c.1281G>A(p.Thr427Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T427T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

JUP
NM_002230.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.66

Publications

0 publications found

Variant links:

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

JUP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 17-41763199-C-T is Benign according to our data. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41763199-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 137612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.66 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000394 (6/152224) while in subpopulation EAS AF = 0.000963 (5/5192). AF 95% confidence interval is 0.000379. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4 link	c.1281G>A	p.Thr427Thr	synonymous_variant	Exon 8 of 14	ENST00000393931.8	NP_002221.1	P14923A0A0S2Z487

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
JUP	ENST00000393931.8 link	c.1281G>A	p.Thr427Thr	synonymous_variant	Exon 8 of 14	1	NM_002230.4	ENSP00000377508.3	P14923
JUP	ENST00000310706.9 link	c.1281G>A	p.Thr427Thr	synonymous_variant	Exon 8 of 15	1		ENSP00000311113.5	P14923
JUP	ENST00000393930.5 link	c.1281G>A	p.Thr427Thr	synonymous_variant	Exon 8 of 15	5		ENSP00000377507.1	P14923
JUP	ENST00000585793.1 link	n.-122G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000111

AC:

AN:

251466

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000730

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000963

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 10, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jan 17, 2022

Phosphorus, Inc.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This synonymous variant has an entry in ClinVar (137612) NM_002230.4 (JUP): c.1281G>A (p.Thr427=) and has occurred in GnomAD with a total MAF of 0.0106% and highest MAF of 0.1449% in the East Asian population. This position is not conserved. In silico splicing algorithm was unavailable, however it is not predicted to impact splicing due to its distance from the splice site. No functional studies were performed to confirm this prediction. The variant has not occurred in literature associated with disease. Considering the above evidence, this variant has been classified as Likely Benign. -

Cardiovascular phenotype

Benign:1

Jul 06, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.9

(source)

DANN

Benign

0.64

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over