rs149926974

Variant names:

• chr17-41758805-T-C
• rs149926974
• NM_002230.4:c.1563A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002230.4(JUP):​c.1563A>G​(p.Ala521Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,611,740 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0070 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (93 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -7.14
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 17-41758805-T-C is Benign according to our data. Variant chr17-41758805-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45837.
• BP7: Synonymous conserved (PhyloP=-7.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00703 (1070/152290) while in subpopulation NFE AF = 0.00638 (434/68016). AF 95% confidence interval is 0.00589. There are 11 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR,AD gene

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.1563A>G	p.Ala521Ala	synonymous	Exon 9 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1563A>G	p.Ala521Ala	synonymous	Exon 9 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1563A>G	p.Ala521Ala	synonymous	Exon 9 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.1563A>G	p.Ala521Ala	synonymous	Exon 9 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1563A>G	p.Ala521Ala	synonymous	Exon 9 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1563A>G	p.Ala521Ala	synonymous	Exon 9 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1070 AN: 152172 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0542

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00638

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00665 AC: 1624 AN: 244152 AF XY: 0.00649

Gnomad AFR exome AF: 0.000646

Gnomad AMR exome AF: 0.000938

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0484

Gnomad NFE exome AF: 0.00495

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00506 AC: 7384 AN: 1459450 Hom.: 93 Cov.: 32 AF XY: 0.00505 AC XY: 3662 AN XY: 725812

African (AFR) AF: 0.000508 AC: 17 AN: 33468

American (AMR) AF: 0.000787 AC: 35 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.000767 AC: 20 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000826 AC: 71 AN: 85918

European-Finnish (FIN) AF: 0.0462 AC: 2451 AN: 52996

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5738

European-Non Finnish (NFE) AF: 0.00413 AC: 4590 AN: 1110876

Other (OTH) AF: 0.00320 AC: 193 AN: 60238

GnomAD4 genome AF: 0.00703 AC: 1070 AN: 152290 Hom.: 11 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74478

African (AFR) AF: 0.000890 AC: 37 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.0542 AC: 576 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00638 AC: 434 AN: 68016

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00534 Hom.: 4

Bravo AF: 0.00240

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Naxos disease (1)
-	-	1	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.35
DANN	Benign	0.32
PhyloP100		-7.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Mutation Taster		=99/1	polymorphism

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: rs149926974; hg19: chr17-39915057;