17-21011188-C-A

Variant names:

• chr17-21011188-C-A
• rs774736082
• NM_015276.2:c.1066G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015276.2(USP22):​c.1066G>T​(p.Val356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. V356M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: USP22 NM_015276.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 0 publications found

Genes affected

USP22 (HGNC:12621): (ubiquitin specific peptidase 22) Enables enzyme binding activity; nuclear receptor coactivator activity; and thiol-dependent deubiquitinase. Contributes to H4 histone acetyltransferase activity. Involved in positive regulation of mitotic cell cycle; positive regulation of transcription, DNA-templated; and protein modification by small protein conjugation or removal. Part of SAGA complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050479084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015276.2. 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
	USP22	NM_015276.2	MANE Select	c.1066G>T	p.Val356Leu	missense	Exon 8 of 13	NP_056091.1	Q9UPT9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP22	ENST00000261497.9	TSL:1 MANE Select	c.1066G>T	p.Val356Leu	missense	Exon 8 of 13	ENSP00000261497.4	Q9UPT9-1
	USP22	ENST00000537526.6	TSL:1	c.1030G>T	p.Val344Leu	missense	Exon 8 of 13	ENSP00000440950.2	Q9UPT9-2
	USP22	ENST00000478443.1	TSL:1	n.427G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458986 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725626

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85870

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110298

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.022
DANN	Benign	0.56
DEOGEN2	Benign	0.037	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.025	N
PhyloP100		0.076
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.023
Sift	Benign	0.58	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.30		Loss of loop (P = 0.1242)
MVP		0.25
MPC		0.88
ClinPred		0.024	T
GERP RS		-1.9
Varity_R		0.029
gMVP		0.15

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

dbSNP: rs774736082; hg19: chr17-20914501;