chr11-119360215-C-G

Variant names:

• chr11-119360215-C-G
• NM_004205.5:c.794G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004205.5(USP2):​c.794G>C​(p.Gly265Ala) 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: USP2 NM_004205.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.24
• Publications: 0 publications found

Genes affected

USP2 (HGNC:12618): (ubiquitin specific peptidase 2) This gene encodes a member of the family of de-ubiquitinating enzymes, which belongs to the peptidase C19 superfamily. The encoded protein is a ubiquitin-specific protease which is required for TNF-alpha (tumor necrosis factor alpha) -induced NF-kB (nuclear factor kB) signaling. This protein deubiquitinates polyubiquitinated target proteins such as fatty acid synthase, murine double minute 2 (MDM2), MDM4/MDMX and cyclin D1. MDM2 and MDM4 are negative regulators of the p53 tumor suppressor and cyclin D1 is required for cell cycle G1/S transition. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

USP2-AS1 (HGNC:48673): (USP2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004205.5. 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
	USP2	NM_004205.5	MANE Select	c.794G>C	p.Gly265Ala	missense	Exon 3 of 13	NP_004196.4
	USP2	NM_171997.3		c.167G>C	p.Gly56Ala	missense	Exon 2 of 12	NP_741994.1	O75604-4
	USP2	NM_001243759.2		c.65G>C	p.Gly22Ala	missense	Exon 2 of 12	NP_001230688.1	O75604-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP2	ENST00000260187.7	TSL:1 MANE Select	c.794G>C	p.Gly265Ala	missense	Exon 3 of 13	ENSP00000260187.2	O75604-1
	USP2	ENST00000525735.1	TSL:1	c.167G>C	p.Gly56Ala	missense	Exon 2 of 12	ENSP00000436952.1	O75604-4
	USP2	ENST00000455332.6	TSL:1	c.65G>C	p.Gly22Ala	missense	Exon 2 of 12	ENSP00000407842.2	O75604-3

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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.83		Loss of catalytic residue at G265 (P = 0.1231)
MVP		0.58
MPC		1.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.79
Mutation Taster		=31/69	disease causing

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

Other links and lift over

hg19: chr11-119230925;