12-6856576-C-G

Variant names:

• chr12-6856576-C-G
• rs2238114
• NM_001098536.2:c.584+126C>G

Variant summary

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

The NM_001098536.2(USP5):​c.584+126C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,982 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: USP5 NM_001098536.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39
• Publications: 0 publications found

Genes affected

USP5 (HGNC:12628): (ubiquitin specific peptidase 5) Ubiquitin (see MIM 191339)-dependent proteolysis is a complex pathway of protein metabolism implicated in such diverse cellular functions as maintenance of chromatin structure, receptor function, and degradation of abnormal proteins. A late step of the process involves disassembly of the polyubiquitin chains on degraded proteins into ubiquitin monomers. USP5 disassembles branched polyubiquitin chains by a sequential exo mechanism, starting at the proximal end of the chain (Wilkinson et al., 1995 [PubMed 7578059]).[supplied by OMIM, Mar 2010]

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 (BayesDel_noAF=-0.87).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098536.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP5	NM_001098536.2	MANE Select	c.584+126C>G		intron	N/A	NP_001092006.1
	USP5	NM_003481.3		c.584+126C>G		intron	N/A	NP_003472.2
	USP5	NM_001382591.1		c.584+126C>G		intron	N/A	NP_001369520.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	USP5	ENST00000229268.13	TSL:1 MANE Select	c.584+126C>G		intron	N/A	ENSP00000229268.8
	USP5	ENST00000389231.9	TSL:1	c.584+126C>G		intron	N/A	ENSP00000373883.5
	USP5	ENST00000542087.1	TSL:3	c.357+507C>G		intron	N/A	ENSP00000444668.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390982 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 685802

African (AFR) AF: 0.00 AC: 0 AN: 31808

American (AMR) AF: 0.00 AC: 0 AN: 38554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22234

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.0000131 AC: 1 AN: 76396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077850

Other (OTH) AF: 0.00 AC: 0 AN: 57588

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.027
DANN	Benign	0.13
PhyloP100		-1.4

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: rs2238114; hg19: chr12-6965740;