dbSNP rs774734512: JOSD2:p.Arg123Leu (chr19-50506477-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001270639.2(JOSD2):c.368G>T(p.Arg123Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,572,726 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R123Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

JOSD2
NM_001270639.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

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]

JOSD2 links:

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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 rank	MANE	Protein	UniProt
JOSD2	NM_001270639.2 link	c.368G>T	p.Arg123Leu	missense_variant	Exon 4 of 5	ENST00000598418.6	NP_001257568.1	Q8TAC2-1A0A024R4G2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JOSD2	ENST00000598418.6 link	c.368G>T	p.Arg123Leu	missense_variant	Exon 4 of 5	1	NM_001270639.2	ENSP00000468956.2		Q8TAC2-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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:

0.0000624

AC:

AN:

176416

Hom.:

AF XY:

0.0000832

AC XY:

AN XY:

96128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000573

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000827

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000514

AC:

AN:

1420938

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

703622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000905

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.0000403

Gnomad4 OTH exome

AF:

0.0000681

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

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:

0.0000434

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000341

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.7

M;M;.;.

PrimateAI

Uncertain

0.76

Sift4G

Benign

0.23

T;T;T;T

Polyphen

1.0

D;D;.;.

Vest4

0.61

MutPred

0.58

Loss of MoRF binding (P = 0.0269);Loss of MoRF binding (P = 0.0269);.;Loss of MoRF binding (P = 0.0269);

MVP

0.45

MPC

1.1

ClinPred

0.63

GERP RS

3.2

Varity_R

0.83

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over