17-41757415-A-T

Variant names:

• chr17-41757415-A-T
• rs782632671
• NM_002230.4:c.2046T>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_002230.4(JUP):​c.2046T>A​(p.Ala682Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A682A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: JUP NM_002230.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001079
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.132
• Publications: 0 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-41757415-A-T is Benign according to our data. Variant chr17-41757415-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 263755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.132 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000013 (19/1461876) while in subpopulation AMR AF = 0.000425 (19/44724). AF 95% confidence interval is 0.000277. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 38. 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	NM_002230.4	MANE Select	c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 14	NP_002221.1
	JUP	NM_001352773.2		c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 14	NP_001339702.1
	JUP	NM_001352774.2		c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 15	NP_001339703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JUP	ENST00000393931.8	TSL:1 MANE Select	c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 14	ENSP00000377508.3
	JUP	ENST00000310706.9	TSL:1	c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 15	ENSP00000311113.5
	JUP	ENST00000393930.5	TSL:5	c.2046T>A	p.Ala682Ala	splice_region synonymous	Exon 12 of 15	ENSP00000377507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000716 AC: 18 AN: 251476 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461876 Hom.: 0 Cov.: 38 AF XY: 0.00000413 AC XY: 3 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiovascular phenotype Benign:1

Sep 04, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Benign:1

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.3
DANN	Benign	0.81
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.050		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: rs782632671; hg19: chr17-39913667;