Genetic Variant DESI2:p.Thr151Arg (chr1-244705656-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_016076.5(DESI2):c.452C>G(p.Thr151Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T151M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DESI2
NM_016076.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.84

Publications

0 publications found

Variant links:

Genes affected

DESI2 (HGNC:24264): (desumoylating isopeptidase 2) Enables Lys48-specific deubiquitinase activity; Lys63-specific deubiquitinase activity; and thiol-dependent deubiquitinase. Predicted to be involved in protein deubiquitination. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

DESI2 links:

ENSG00000301033 (HGNC:):

ENSG00000301033 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016076.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DESI2	NM_016076.5	MANE Select	c.452C>G	p.Thr151Arg	missense	Exon 5 of 5	NP_057160.2
DESI2	NM_001297746.2		c.353C>G	p.Thr118Arg	missense	Exon 4 of 4	NP_001284675.1	Q9BSY9-2
DESI2	NR_123735.2		n.635C>G		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DESI2	ENST00000302550.16	TSL:1 MANE Select	c.452C>G	p.Thr151Arg	missense	Exon 5 of 5	ENSP00000306528.11	Q9BSY9-1
DESI2	ENST00000263831.11	TSL:1	c.353C>G	p.Thr118Arg	missense	Exon 4 of 4	ENSP00000263831.7	Q9BSY9-2
DESI2	ENST00000859654.1		c.512C>G	p.Thr171Arg	missense	Exon 6 of 6	ENSP00000529713.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461836

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111988

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.1

PhyloP100

7.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.43

Sift

Benign

0.26

Sift4G

Benign

0.50

Polyphen

0.93

Vest4

0.82

MutPred

0.42

Loss of ubiquitination at K147 (P = 0.046)

MVP

0.62

MPC

1.5

ClinPred

0.97

GERP RS

6.2

Varity_R

0.47

gMVP

0.90

Mutation Taster

=17/83

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over