chr17-41769557-G-T

Variant names:

• chr17-41769557-G-T
• rs782770278
• NM_002230.4:c.329C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002230.4(JUP):​c.329C>A​(p.Ala110Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,726 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A110V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.447
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17537421).

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.329C>A	p.Ala110Asp	missense	Exon 3 of 14	NP_002221.1	P14923
	JUP	NM_001352773.2		c.329C>A	p.Ala110Asp	missense	Exon 3 of 14	NP_001339702.1	P14923
	JUP	NM_001352774.2		c.329C>A	p.Ala110Asp	missense	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.329C>A	p.Ala110Asp	missense	Exon 3 of 14	ENSP00000377508.3	P14923
	JUP	ENST00000310706.9	TSL:1	c.329C>A	p.Ala110Asp	missense	Exon 3 of 15	ENSP00000311113.5	P14923
	JUP	ENST00000393930.5	TSL:5	c.329C>A	p.Ala110Asp	missense	Exon 3 of 15	ENSP00000377507.1	P14923

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455726 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 723816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 43726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25934

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 85156

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110084

Other (OTH) AF: 0.00 AC: 0 AN: 60114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.0097
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.45
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.14	B
Vest4		0.17
MutPred		0.39		Gain of disorder (P = 0.0732)
MVP		0.75
MPC		0.14
ClinPred		0.54	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs782770278; hg19: chr17-39925809;