Genetic Variant USP2:p.Thr579Ala (chr11-119356918-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004205.5(USP2):c.1735A>G(p.Thr579Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000356 in 1,406,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

USP2
NM_004205.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.82

Publications

0 publications found

Variant links:

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 links:

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

USP2-AS1 links:

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ACMG classification

Classification was made for transcript

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=0.21371448).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP2	NM_004205.5 link	c.1735A>G	p.Thr579Ala	missense_variant	Exon 13 of 13	ENST00000260187.7	NP_004196.4	O75604-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP2	ENST00000260187.7 link	c.1735A>G	p.Thr579Ala	missense_variant	Exon 13 of 13	1	NM_004205.5	ENSP00000260187.2		O75604-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000356

AC:

AN:

1406420

Hom.:

Cov.:

AF XY:

0.00000288

AC XY:

AN XY:

694288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32414

American (AMR)

AF:

0.00

AC:

AN:

36190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25220

East Asian (EAS)

AF:

0.00

AC:

AN:

37170

South Asian (SAS)

AF:

0.00

AC:

AN:

79838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4200

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1083772

Other (OTH)

AF:

0.00

AC:

AN:

58218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1735A>G (p.T579A) alteration is located in exon 13 (coding exon 12) of the USP2 gene. This alteration results from a A to G substitution at nucleotide position 1735, causing the threonine (T) at amino acid position 579 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.083

.;T;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.0087

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

.;M;.

PhyloP100

3.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.073

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.0030, 0.046

.;B;B

Vest4

0.22

MutPred

0.40

.;Loss of glycosylation at T579 (P = 0.0222);.;

MVP

0.44

MPC

0.31

ClinPred

0.85

GERP RS

3.3

Varity_R

0.35

gMVP

0.27

Mutation Taster

=52/48

polymorphism

(source)

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

Publications

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chr11-119356918-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over