chr11-119356842-C-A

Variant names:

• chr11-119356842-C-A
• rs777131363
• NM_004205.5:c.1811G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004205.5(USP2):​c.1811G>T​(p.Arg604Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,410,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R604P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP2 NM_004205.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.16
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37955374).

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.1811G>T	p.Arg604Leu	missense	Exon 13 of 13	NP_004196.4
	USP2	NM_171997.3		c.1184G>T	p.Arg395Leu	missense	Exon 12 of 12	NP_741994.1	O75604-4
	USP2	NM_001243759.2		c.1082G>T	p.Arg361Leu	missense	Exon 12 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.1811G>T	p.Arg604Leu	missense	Exon 13 of 13	ENSP00000260187.2	O75604-1
	USP2	ENST00000525735.1	TSL:1	c.1184G>T	p.Arg395Leu	missense	Exon 12 of 12	ENSP00000436952.1	O75604-4
	USP2	ENST00000455332.6	TSL:1	c.1082G>T	p.Arg361Leu	missense	Exon 12 of 12	ENSP00000407842.2	O75604-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000581 AC: 1 AN: 172122 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000750

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1410448 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696492

African (AFR) AF: 0.00 AC: 0 AN: 32638

American (AMR) AF: 0.00 AC: 0 AN: 36420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25190

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37478

South Asian (SAS) AF: 0.00 AC: 0 AN: 80004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4850

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085650

Other (OTH) AF: 0.00 AC: 0 AN: 58406

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.95	P
Vest4		0.52
MutPred		0.33		Loss of solvent accessibility (P = 0.0249)
MVP		0.56
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.78
gMVP		0.39
Mutation Taster		=47/53	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: rs777131363; hg19: chr11-119227552; COSMIC: COSV104586512; COSMIC: COSV104586512;