19-50507667-C-T

Variant summary

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

The ENST00000598418.6(JOSD2):​c.179G>A​(p.Arg60His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000054 in 1,611,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

JOSD2
ENST00000598418.6 missense

Scores

1
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.712
Variant links:
Genes affected
JOSD2 (HGNC:28853): (Josephin domain containing 2) This gene encodes a protein containing a Josephin domain. Josephin domain-containing proteins are deubiquitinating enzymes which catalyze the hydrolysis of the bond between the C-terminal glycine of the ubiquitin peptide and protein substrates. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
JOSD2NM_001270639.2 linkuse as main transcriptc.179G>A p.Arg60His missense_variant 3/5 ENST00000598418.6 NP_001257568.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
JOSD2ENST00000598418.6 linkuse as main transcriptc.179G>A p.Arg60His missense_variant 3/51 NM_001270639.2 ENSP00000468956 P1Q8TAC2-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152138
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000401
AC:
10
AN:
249124
Hom.:
0
AF XY:
0.0000518
AC XY:
7
AN XY:
135184
show subpopulations
Gnomad AFR exome
AF:
0.0000619
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.0000955
Gnomad NFE exome
AF:
0.0000534
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000562
AC:
82
AN:
1459788
Hom.:
0
Cov.:
31
AF XY:
0.0000592
AC XY:
43
AN XY:
726208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000388
Gnomad4 NFE exome
AF:
0.0000648
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152138
Hom.:
0
Cov.:
30
AF XY:
0.0000404
AC XY:
3
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000825
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 13, 2021The c.179G>A (p.R60H) alteration is located in exon 3 (coding exon 2) of the JOSD2 gene. This alteration results from a G to A substitution at nucleotide position 179, causing the arginine (R) at amino acid position 60 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.35
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.11
T;T;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.97
.;D;D
M_CAP
Benign
0.054
D
MetaRNN
Uncertain
0.43
T;T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.9
M;M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.78
T
Sift4G
Benign
0.22
T;T;T
Polyphen
1.0
D;D;.
Vest4
0.64
MVP
0.38
MPC
1.1
ClinPred
0.51
D
GERP RS
3.4
Varity_R
0.64
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs376769993; hg19: chr19-51010924; API