Genetic Variant DESI2:p.Leu81Val (chr1-244691910-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016076.5(DESI2):c.241C>G(p.Leu81Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000125 in 1,595,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DESI2
NM_016076.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19672245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DESI2	NM_016076.5 link	c.241C>G	p.Leu81Val	missense_variant	Exon 4 of 5	ENST00000302550.16	NP_057160.2	Q9BSY9-1A0A024R5P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DESI2	ENST00000302550.16 link	c.241C>G	p.Leu81Val	missense_variant	Exon 4 of 5	1	NM_016076.5	ENSP00000306528.11	Q9BSY9-1
DESI2	ENST00000263831.11 link	c.142C>G	p.Leu48Val	missense_variant	Exon 3 of 4	1		ENSP00000263831.7	Q9BSY9-2
DESI2	ENST00000418162.1 link	c.292C>G	p.Leu98Val	missense_variant	Exon 4 of 4	5		ENSP00000394555.1	B1APK7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000427

AC:

AN:

234384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

127426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000912

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1443414

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718094

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151866

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.241C>G (p.L81V) alteration is located in exon 4 (coding exon 4) of the DESI2 gene. This alteration results from a C to G substitution at nucleotide position 241, causing the leucine (L) at amino acid position 81 to be replaced by a valine (V). 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

0.089

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

T;.;T

Eigen

Benign

0.013

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.0016

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.60

N;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.49

N;N;N

REVEL

Benign

0.064

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.23

MutPred

0.36

Loss of stability (P = 0.1454);.;.;

MVP

0.14

MPC

1.1

ClinPred

0.42

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over