rs200976464

Variant names:

• chr17-41769589-C-T
• rs200976464
• NM_002230.4:c.297G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-41769589-C-T
• chr17-41769589-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS1

The NM_002230.4(JUP):​c.297G>A​(p.Ser99Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000551 in 1,605,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: JUP NM_002230.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -6.29
• 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 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 17-41769589-C-T is Benign according to our data. Variant chr17-41769589-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45848.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000512 (78/152338) while in subpopulation AMR AF = 0.00183 (28/15304). AF 95% confidence interval is 0.0013. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 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.297G>A	p.Ser99Ser	synonymous	Exon 3 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.297G>A	p.Ser99Ser	synonymous	Exon 3 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.297G>A	p.Ser99Ser	synonymous	Exon 3 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.297G>A	p.Ser99Ser	synonymous	Exon 3 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.297G>A	p.Ser99Ser	synonymous	Exon 3 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.297G>A	p.Ser99Ser	synonymous	Exon 3 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000658 AC: 152 AN: 230984 AF XY: 0.000696

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00263

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000575

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000555 AC: 807 AN: 1453420 Hom.: 0 Cov.: 34 AF XY: 0.000581 AC XY: 420 AN XY: 722370

African (AFR) AF: 0.0000897 AC: 3 AN: 33432

American (AMR) AF: 0.000953 AC: 41 AN: 43018

Ashkenazi Jewish (ASJ) AF: 0.00209 AC: 54 AN: 25784

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39360

South Asian (SAS) AF: 0.00116 AC: 98 AN: 84610

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52370

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5750

European-Non Finnish (NFE) AF: 0.000509 AC: 565 AN: 1109006

Other (OTH) AF: 0.000549 AC: 33 AN: 60090

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000658 Hom.: 0

Bravo AF: 0.000442

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.2
DANN	Benign	0.78
PhyloP100		-6.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200976464; hg19: chr17-39925841;