2-232024329-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_152383.5(DIS3L2):c.263C>T(p.Pro88Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000793 in 1,597,398 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00080 ( 2 hom. )

Consequence

DIS3L2
NM_152383.5 missense, splice_region

Scores

Splicing: ADA: 0.5867

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 6.14

Publications

9 publications found

Variant links:

Genes affected

DIS3L2 (HGNC:28648): (DIS3 like 3'-5' exoribonuclease 2) The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]

DIS3L2 Gene-Disease associations (from GenCC):

Perlman syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

DIS3L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01389581).

BP6

Variant 2-232024329-C-T is Benign according to our data. Variant chr2-232024329-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334929.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000756 (115/152188) while in subpopulation SAS AF = 0.00187 (9/4818). AF 95% confidence interval is 0.000974. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.263C>T	p.Pro88Leu	missense_variant, splice_region_variant	Exon 4 of 21	ENST00000325385.12	NP_689596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.263C>T	p.Pro88Leu	missense_variant, splice_region_variant	Exon 4 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000812

AC:

195

AN:

240294

AF XY:

0.000876

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000125

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000577

Gnomad FIN exome

AF:

0.0000466

Gnomad NFE exome

AF:

0.000694

Gnomad OTH exome

AF:

0.00137

GnomAD4 exome

AF:

0.000796

AC:

1151

AN:

1445210

Hom.:

Cov.:

AF XY:

0.000885

AC XY:

636

AN XY:

718728

show subpopulations

African (AFR)

AF:

0.000549

AC:

AN:

32764

American (AMR)

AF:

0.000257

AC:

AN:

42768

Ashkenazi Jewish (ASJ)

AF:

0.000232

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39266

South Asian (SAS)

AF:

0.00312

AC:

257

AN:

82324

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.000699

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000731

AC:

806

AN:

1103312

Other (OTH)

AF:

0.000735

AC:

AN:

59838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152188

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41532

American (AMR)

AF:

0.000981

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00187

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000735

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00112

AC:

ESP6500EA

AF:

0.000989

AC:

ExAC

AF:

0.000903

AC:

109

Asia WGS

AF:

0.00173

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jun 15, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DIS3L2-related disorder

Benign:1

Oct 11, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DIS3L2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;.;T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;.;D;.

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.6

M;M;M;.;M

PhyloP100

6.1

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.4

D;D;D;D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0080

D;D;D;D;D

Sift4G

Uncertain

0.036

D;D;D;D;D

Polyphen

1.0, 0.99

.;D;D;.;D

Vest4

0.80

MVP

0.35

MPC

0.71

ClinPred

0.055

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.53

gMVP

0.54

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.59

dbscSNV1_RF

Benign

0.53

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over