rs2230407

Variant names:

• chr17-41767421-G-A
• rs2230407
• NM_002230.4:c.867C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-41767421-G-A
• chr17-41767421-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002230.4(JUP):​c.867C>T​(p.Thr289Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,614,166 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (58 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (54 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -4.94
• Publications: 5 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-41767421-G-A is Benign according to our data. Variant chr17-41767421-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.94 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

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.867C>T	p.Thr289Thr	synonymous	Exon 5 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.867C>T	p.Thr289Thr	synonymous	Exon 5 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.867C>T	p.Thr289Thr	synonymous	Exon 5 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.867C>T	p.Thr289Thr	synonymous	Exon 5 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.867C>T	p.Thr289Thr	synonymous	Exon 5 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.867C>T	p.Thr289Thr	synonymous	Exon 5 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.0145 AC: 2202 AN: 152180 Hom.: 54 Cov.: 31

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00368 AC: 925 AN: 251408 AF XY: 0.00263

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00146 AC: 2137 AN: 1461866 Hom.: 54 Cov.: 46 AF XY: 0.00125 AC XY: 908 AN XY: 727232

African (AFR) AF: 0.0549 AC: 1839 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000513 AC: 57 AN: 1112010

Other (OTH) AF: 0.00265 AC: 160 AN: 60394

GnomAD4 genome AF: 0.0146 AC: 2222 AN: 152300 Hom.: 58 Cov.: 31 AF XY: 0.0144 AC XY: 1070 AN XY: 74468

African (AFR) AF: 0.0517 AC: 2149 AN: 41554

American (AMR) AF: 0.00288 AC: 44 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.00639 Hom.: 11

Bravo AF: 0.0165

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiac arrhythmia (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	-0.71
CADD	Benign	1.2
DANN	Benign	0.81
PhyloP100		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
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: rs2230407; hg19: chr17-39923673;