NM_002230.4:c.909+49T>C

Variant names:

• chr17-41767330-A-G
• rs77529236
• NM_002230.4:c.909+49T>C

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.909+49T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,522,284 control chromosomes in the GnomAD database, including 1,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (559 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (480 hom.)
• Consequence: JUP NM_002230.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.211
• Publications: 1 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 (BayesDel_noAF=-0.97).
• BP6: Variant 17-41767330-A-G is Benign according to our data. Variant chr17-41767330-A-G is described in ClinVar as Benign. ClinVar VariationId is 261477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.909+49T>C		intron	N/A	NP_002221.1
	JUP	NM_001352773.2		c.909+49T>C		intron	N/A	NP_001339702.1
	JUP	NM_001352774.2		c.909+49T>C		intron	N/A	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.909+49T>C		intron	N/A	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.909+49T>C		intron	N/A	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.909+49T>C		intron	N/A	ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.0463 AC: 7043 AN: 152136 Hom.: 552 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0339

GnomAD2 exomes AF: 0.0124 AC: 3072 AN: 246920 AF XY: 0.00925

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00989

Gnomad ASJ exome AF: 0.000700

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000384

Gnomad OTH exome AF: 0.00594

GnomAD4 exome AF: 0.00486 AC: 6653 AN: 1370030 Hom.: 480 Cov.: 22 AF XY: 0.00409 AC XY: 2809 AN XY: 686602

African (AFR) AF: 0.162 AC: 5111 AN: 31510

American (AMR) AF: 0.0111 AC: 495 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.000470 AC: 12 AN: 25550

East Asian (EAS) AF: 0.00 AC: 0 AN: 39360

South Asian (SAS) AF: 0.000344 AC: 29 AN: 84304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51590

Middle Eastern (MID) AF: 0.00540 AC: 28 AN: 5186

European-Non Finnish (NFE) AF: 0.000269 AC: 277 AN: 1030628

Other (OTH) AF: 0.0122 AC: 701 AN: 57408

GnomAD4 genome AF: 0.0465 AC: 7075 AN: 152254 Hom.: 559 Cov.: 32 AF XY: 0.0452 AC XY: 3362 AN XY: 74450

African (AFR) AF: 0.160 AC: 6635 AN: 41536

American (AMR) AF: 0.0204 AC: 312 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68022

Other (OTH) AF: 0.0336 AC: 71 AN: 2116

Alfa AF: 0.0212 Hom.: 57

Bravo AF: 0.0531

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.0
DANN	Benign	0.49
PhyloP100		0.21
Mutation Taster		=100/0	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: rs77529236; hg19: chr17-39923582;