rs797044796

Positions:

• chr17-41763156-T-C
• chr17-41763156-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002230.4(JUP):​c.1324A>G​(p.Ile442Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.992

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24046549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JUP	NM_002230.4	c.1324A>G	p.Ile442Val	missense_variant	8/14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.1324A>G	p.Ile442Val	missense_variant	8/14	1	NM_002230.4	ENSP00000377508	P1
JUP	ENST00000310706.9	c.1324A>G	p.Ile442Val	missense_variant	8/15	1		ENSP00000311113	P1
JUP	ENST00000393930.5	c.1324A>G	p.Ile442Val	missense_variant	8/15	5		ENSP00000377507	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.22	T;T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.41	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.040	B;B;B
Vest4		0.30
MutPred		0.65		Gain of disorder (P = 0.2911);Gain of disorder (P = 0.2911);Gain of disorder (P = 0.2911);
MVP		0.73
MPC		0.42
ClinPred		0.35	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.26
gMVP		0.12

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: rs142213474; hg19: chr17-39919408;