2-232024329-C-T

Position:

chr2-232024329-C-T

Variant summary

Our verdict is Benign. Variant got -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).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 334929.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr2-232024329-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5 linkuse as main transcript	c.263C>T	p.Pro88Leu	missense_variant, splice_region_variant	4/21	ENST00000325385.12	NP_689596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.263C>T	p.Pro88Leu	missense_variant, splice_region_variant	4/21	5	NM_152383.5	ENSP00000315569	P1	Q8IYB7-1

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

GnomAD3 exomes

AF:

0.000812

AC:

195

AN:

240294

Hom.:

AF XY:

0.000876

AC XY:

114

AN XY:

130084

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 SAS exome

AF:

0.00324

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

Gnomad4 AFR exome

AF:

0.000549

Gnomad4 AMR exome

AF:

0.000257

Gnomad4 ASJ exome

AF:

0.000232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00312

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.000731

Gnomad4 OTH exome

AF:

0.000735

GnomAD4 genome

AF:

0.000756

AC:

115

AN:

152188

Hom.:

Cov.:

AF XY:

0.000847

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.000963

Gnomad4 AMR

AF:

0.000981

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000660

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

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 24, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 15, 2022	- -

DIS3L2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2019

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

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

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

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

MutationTaster

Benign

1.0

D;D;D;D;D

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

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

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