17-41758746-T-G

Variant summary

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

The NM_002230.4(JUP):ā€‹c.1622A>Cā€‹(p.His541Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,454,212 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000041 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

JUP
NM_002230.4 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JUPNM_002230.4 linkuse as main transcriptc.1622A>C p.His541Pro missense_variant 9/14 ENST00000393931.8 NP_002221.1 P14923A0A0S2Z487

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JUPENST00000393931.8 linkuse as main transcriptc.1622A>C p.His541Pro missense_variant 9/141 NM_002230.4 ENSP00000377508.3 P14923
JUPENST00000310706.9 linkuse as main transcriptc.1622A>C p.His541Pro missense_variant 9/151 ENSP00000311113.5 P14923
JUPENST00000393930.5 linkuse as main transcriptc.1622A>C p.His541Pro missense_variant 9/155 ENSP00000377507.1 P14923
JUPENST00000585793.1 linkuse as main transcriptn.220A>C non_coding_transcript_exon_variant 2/32

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152062
Hom.:
0
Cov.:
32
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000427
AC:
1
AN:
234452
Hom.:
0
AF XY:
0.00000786
AC XY:
1
AN XY:
127238
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000573
Gnomad SAS 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:
0.00000413
AC:
6
AN:
1454212
Hom.:
0
Cov.:
32
AF XY:
0.00000415
AC XY:
3
AN XY:
722870
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000152
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
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152062
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74292
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 25, 2022The p.H541P variant (also known as c.1622A>C), located in coding exon 8 of the JUP gene, results from an A to C substitution at nucleotide position 1622. The histidine at codon 541 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.23
CADD
Uncertain
23
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.46
T;T;T
Eigen
Benign
-0.091
Eigen_PC
Benign
0.087
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.80
.;.;T
M_CAP
Benign
0.056
D
MetaRNN
Uncertain
0.60
D;D;D
MetaSVM
Benign
-0.85
T
MutationAssessor
Benign
1.5
L;L;L
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-2.3
N;N;N
REVEL
Benign
0.22
Sift
Uncertain
0.0070
D;D;D
Sift4G
Benign
0.079
T;T;T
Polyphen
0.0040
B;B;B
Vest4
0.70
MutPred
0.48
Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP
0.62
MPC
0.77
ClinPred
0.40
T
GERP RS
5.1
Varity_R
0.84
gMVP
0.81

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs782449369; hg19: chr17-39914998; API