NM_002230.4:c.2089A>T

Variant names:

• chr17-41755893-T-A
• rs1126821
• NM_002230.4:c.2089A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002230.4(JUP):​c.2089A>T​(p.Met697Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,605,478 control chromosomes in the GnomAD database, including 412,210 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34334 hom., cov: 30)
  • Exomes 𝑓: 0.72 (377876 hom.)
• Consequence: JUP NM_002230.4 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 1.03
• Publications: 43 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7191055E-6).
• BP6: Variant 17-41755893-T-A is Benign according to our data. Variant chr17-41755893-T-A is described in ClinVar as Benign. ClinVar VariationId is 21304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.74 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.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 14	NP_002221.1
	JUP	NM_001352773.2		c.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 15	NP_001339703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.2089A>T	p.Met697Leu	missense splice_region	Exon 14 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100923 AN: 151790 Hom.: 34303 Cov.: 30

Gnomad AFR AF: 0.601

Gnomad AMI AF: 0.817

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.721

Gnomad FIN AF: 0.648

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.745

Gnomad OTH AF: 0.665

GnomAD2 exomes AF: 0.647 AC: 158651 AN: 245276 AF XY: 0.664

Gnomad AFR exome AF: 0.598

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.700

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.736

Gnomad OTH exome AF: 0.671

GnomAD4 exome AF: 0.716 AC: 1040678 AN: 1453570 Hom.: 377876 Cov.: 52 AF XY: 0.719 AC XY: 518649 AN XY: 721836

African (AFR) AF: 0.596 AC: 19886 AN: 33342

American (AMR) AF: 0.466 AC: 20611 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.695 AC: 17960 AN: 25850

East Asian (EAS) AF: 0.365 AC: 14393 AN: 39482

South Asian (SAS) AF: 0.732 AC: 62789 AN: 85720

European-Finnish (FIN) AF: 0.658 AC: 34440 AN: 52346

Middle Eastern (MID) AF: 0.714 AC: 4089 AN: 5730

European-Non Finnish (NFE) AF: 0.745 AC: 824565 AN: 1106796

Other (OTH) AF: 0.698 AC: 41945 AN: 60080

GnomAD4 genome AF: 0.665 AC: 101012 AN: 151908 Hom.: 34334 Cov.: 30 AF XY: 0.659 AC XY: 48930 AN XY: 74248

African (AFR) AF: 0.601 AC: 24901 AN: 41414

American (AMR) AF: 0.567 AC: 8656 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2370 AN: 3472

East Asian (EAS) AF: 0.346 AC: 1764 AN: 5104

South Asian (SAS) AF: 0.722 AC: 3474 AN: 4814

European-Finnish (FIN) AF: 0.648 AC: 6854 AN: 10584

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.745 AC: 50623 AN: 67934

Other (OTH) AF: 0.670 AC: 1414 AN: 2112

Alfa AF: 0.709 Hom.: 6823

Bravo AF: 0.649

TwinsUK AF: 0.747 AC: 2769

ALSPAC AF: 0.737 AC: 2842

ESP6500AA AF: 0.615 AC: 2709

ESP6500EA AF: 0.739 AC: 6356

ExAC AF: 0.657 AC: 79707

Asia WGS AF: 0.562 AC: 1954 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Arrhythmogenic right ventricular dysplasia 12 (3)
-	-	2	Naxos disease (2)
-	-	2	not provided (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.69
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0000017	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.63	N
PhyloP100		1.0
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.062
Sift	Benign	0.71	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MutPred		0.17		Loss of helix (P = 0.0093)
MPC		0.45
ClinPred		0.0083	T
GERP RS		1.1
Varity_R		0.13
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

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: rs1126821; hg19: chr17-39912145; COSMIC: COSV60277352; COSMIC: COSV60277352;