17-41755121-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002230.4(JUP):c.*623G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 397,316 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.014 (25 hom., cov: 32)
  • Exomes 𝑓: 0.018 (51 hom.)
• Consequence: JUP NM_002230.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0560

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-41755121-C-T is Benign according to our data. Variant chr17-41755121-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 323152.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2187/152246) while in subpopulation NFE AF= 0.0207 (1409/68012). AF 95% confidence interval is 0.0198. There are 25 homozygotes in gnomad4. There are 1010 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JUP	NM_002230.4	c.*623G>A		3_prime_UTR_variant	14/14	ENST00000393931.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JUP	ENST00000393931.8	c.*623G>A		3_prime_UTR_variant	14/14	1	NM_002230.4	P1
JUP	ENST00000310706.9	c.*326G>A		3_prime_UTR_variant	15/15	1		P1
JUP	ENST00000393930.5	c.*326G>A		3_prime_UTR_variant	15/15	5		P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152128 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0206

Gnomad ASJ AF: 0.0430

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0178 AC: 4368 AN: 245070 Hom.: 51 Cov.: 0 AF XY: 0.0180 AC XY: 2241 AN XY: 124342

Gnomad4 AFR exome AF: 0.00432

Gnomad4 AMR exome AF: 0.0177

Gnomad4 ASJ exome AF: 0.0438

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.00752

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0195

GnomAD4 genome AF: 0.0144 AC: 2187 AN: 152246 Hom.: 25 Cov.: 32 AF XY: 0.0136 AC XY: 1010 AN XY: 74440

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0206

Gnomad4 ASJ AF: 0.0430

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.0207

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0195 Hom.: 3

Bravo AF: 0.0152

Asia WGS AF: 0.00491 AC: 19 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Naxos disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2021

- -

Arrhythmogenic right ventricular dysplasia 12 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.2
Dann	Benign	0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs55634776; hg19: chr17-39911373;