chr19-50507682-C-A

Variant names:

• chr19-50507682-C-A
• rs139728623
• NM_001270639.2:c.164G>T

Variant summary

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

The NM_001270639.2(JOSD2):​c.164G>T​(p.Arg55Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: JOSD2 NM_001270639.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

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]

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=0.11571506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270639.2. 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
	JOSD2	NM_001270639.2	MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	NP_001257568.1	Q8TAC2-1
	JOSD2	NM_001270640.2		c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	NP_001257569.1	Q8TAC2-1
	JOSD2	NM_001270686.2		c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	NP_001257615.1	Q8TAC2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JOSD2	ENST00000598418.6	TSL:1 MANE Select	c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	ENSP00000468956.2	Q8TAC2-1
	JOSD2	ENST00000601423.5	TSL:1	c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	ENSP00000472116.1	Q8TAC2-1
	JOSD2	ENST00000884030.1		c.164G>T	p.Arg55Leu	missense	Exon 3 of 5	ENSP00000554089.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.0055	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.9
PrimateAI	Uncertain	0.68	T
Sift4G	Benign	0.84	T
Polyphen		0.17	B
Vest4		0.44
MutPred		0.30		Loss of disorder (P = 0.0405)
MVP		0.33
MPC		0.41
ClinPred		0.42	T
GERP RS		3.4
Varity_R		0.094
gMVP		0.72
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139728623; hg19: chr19-51010939;