17-41763308-C-T

Variant names:

• chr17-41763308-C-T
• rs199826380
• NM_002230.4:c.1172G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002230.4(JUP):​c.1172G>A​(p.Ser391Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. S391S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:8
• Conservation: PhyloP100: 2.21
• Publications: 7 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015109867).
• BP6: Variant 17-41763308-C-T is Benign according to our data. Variant chr17-41763308-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191672.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000173 (253/1461712) while in subpopulation MID AF = 0.0056 (32/5714). AF 95% confidence interval is 0.00408. There are 0 homozygotes in GnomAdExome4. There are 140 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1172G>A	p.Ser391Asn	missense	Exon 8 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.1172G>A	p.Ser391Asn	missense	Exon 8 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.1172G>A	p.Ser391Asn	missense	Exon 8 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.1172G>A	p.Ser391Asn	missense	Exon 8 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.1172G>A	p.Ser391Asn	missense	Exon 8 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.1172G>A	p.Ser391Asn	missense	Exon 8 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 250442 AF XY: 0.000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000173 AC: 253 AN: 1461712 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 140 AN XY: 727166

African (AFR) AF: 0.000358 AC: 12 AN: 33474

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00560 AC: 32 AN: 5714

European-Non Finnish (NFE) AF: 0.0000719 AC: 80 AN: 1111930

Other (OTH) AF: 0.000414 AC: 25 AN: 60392

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 (2)
-	1	-	Arrhythmogenic right ventricular dysplasia 12 (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	JUP-related disorder (1)
-	1	-	Naxos disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.83
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.37	N
PhyloP100		2.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.092
Sift	Benign	0.59	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.27
MVP		0.42
MPC		0.45
ClinPred		0.014	T
GERP RS		1.8
Varity_R		0.075
gMVP		0.16
Mutation Taster		=83/17	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: rs199826380; hg19: chr17-39919560;