19-50506219-A-G

Variant names:

• chr19-50506219-A-G
• rs1979321653
• NM_001270639.2:c.521T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001270639.2(JOSD2):​c.521T>C​(p.Val174Ala) variant causes a missense change. 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: 3.69
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

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.521T>C	p.Val174Ala	missense	Exon 5 of 5	NP_001257568.1	Q8TAC2-1
	JOSD2	NM_001270640.2		c.521T>C	p.Val174Ala	missense	Exon 5 of 5	NP_001257569.1	Q8TAC2-1
	JOSD2	NM_001270686.2		c.521T>C	p.Val174Ala	missense	Exon 5 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.521T>C	p.Val174Ala	missense	Exon 5 of 5	ENSP00000468956.2	Q8TAC2-1
	JOSD2	ENST00000601423.5	TSL:1	c.521T>C	p.Val174Ala	missense	Exon 5 of 5	ENSP00000472116.1	Q8TAC2-1
	JOSD2	ENST00000884030.1		c.521T>C	p.Val174Ala	missense	Exon 5 of 5	ENSP00000554089.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.82	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.60
MutPred		0.63		Gain of loop (P = 3e-04)
MVP		0.68
MPC		1.1
ClinPred		0.93	D
GERP RS		3.0
Varity_R		0.65
gMVP		0.71
Mutation Taster		=38/62	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

dbSNP: rs1979321653; hg19: chr19-51009476;