19-50510364-A-C

Variant names:

• chr19-50510364-A-C
• NM_001270639.2:c.68T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001270639.2(JOSD2):​c.68T>G​(p.Leu23Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JOSD2 NM_001270639.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

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.68T>G	p.Leu23Arg	missense	Exon 2 of 5	NP_001257568.1	Q8TAC2-1
	JOSD2	NM_001270640.2		c.68T>G	p.Leu23Arg	missense	Exon 2 of 5	NP_001257569.1	Q8TAC2-1
	JOSD2	NM_001270686.2		c.68T>G	p.Leu23Arg	missense	Exon 2 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.68T>G	p.Leu23Arg	missense	Exon 2 of 5	ENSP00000468956.2	Q8TAC2-1
	JOSD2	ENST00000601423.5	TSL:1	c.68T>G	p.Leu23Arg	missense	Exon 2 of 5	ENSP00000472116.1	Q8TAC2-1
	JOSD2	ENST00000884030.1		c.68T>G	p.Leu23Arg	missense	Exon 2 of 5	ENSP00000554089.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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	0.28
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.5
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.85		Gain of disorder (P = 0.0155)
MVP		0.79
MPC		1.2
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.84
gMVP		0.95
Mutation Taster		=39/61	disease causing

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

Other links and lift over

hg19: chr19-51013621;