rs139552714

Variant names:

• chr17-41769115-G-A
• rs139552714
• NM_002230.4:c.561C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41769115-G-A
• chr17-41769115-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_002230.4(JUP):​c.561C>T​(p.Ala187Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000639 in 1,611,504 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A187A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: -8.75
• 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 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-41769115-G-A is Benign according to our data. Variant chr17-41769115-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468756.
• BP7: Synonymous conserved (PhyloP=-8.75 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 14	NP_002221.1
	JUP	NM_001352773.2		c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 15	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.561C>T	p.Ala187Ala	synonymous	Exon 4 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000405 AC: 10 AN: 246728 AF XY: 0.0000523

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: 0.0000530

Gnomad NFE exome AF: 0.0000801

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000637 AC: 93 AN: 1459322 Hom.: 0 Cov.: 33 AF XY: 0.0000565 AC XY: 41 AN XY: 726014

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000196 AC: 1 AN: 51042

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.0000791 AC: 88 AN: 1111932

Other (OTH) AF: 0.0000331 AC: 2 AN: 60346

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.0000965 AC: 4 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000716 Hom.: 0

Bravo AF: 0.0000604

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.92
DANN	Benign	0.90
PhyloP100		-8.8

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: rs139552714; hg19: chr17-39925367;