rs1174909809

Variant names:

• chr11-119356921-C-A
• rs1174909809
• NM_004205.5:c.1732G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-119356921-C-A
• chr11-119356921-C-T

Variant summary

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

The NM_004205.5(USP2):​c.1732G>T​(p.Val578Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000142 in 1,405,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. V578I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP2 NM_004205.5 missense, splice_region
• Scores: Splicing: ADA: 0.9753
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.59
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USP2	NM_004205.5	c.1732G>T	p.Val578Phe	missense_variant, splice_region_variant	Exon 13 of 13	ENST00000260187.7	NP_004196.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USP2	ENST00000260187.7	c.1732G>T	p.Val578Phe	missense_variant, splice_region_variant	Exon 13 of 13	1	NM_004205.5	ENSP00000260187.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1405502 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 693748

African (AFR) AF: 0.00 AC: 0 AN: 32350

American (AMR) AF: 0.00 AC: 0 AN: 36132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 37070

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79762

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4176

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083264

Other (OTH) AF: 0.00 AC: 0 AN: 58190

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Benign	0.13	N
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.0	.;H;.
PhyloP100		5.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.83
MutPred		0.78		.;Loss of glycosylation at T579 (P = 0.1133);.;
MVP		0.76
MPC		1.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.72
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.80
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: rs1174909809; hg19: chr11-119227631;