2-232130729-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001257282.2(DIS3L2):c.712T>G(p.Tyr238Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,613,292 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 25 hom. )

Consequence

DIS3L2
NM_001257282.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.560

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035758317).

BP6

Variant 2-232130729-T-G is Benign according to our data. Variant chr2-232130729-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 241983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232130729-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0033 (503/152242) while in subpopulation NFE AF= 0.00345 (235/68018). AF 95% confidence interval is 0.00309. There are 1 homozygotes in gnomad4. There are 277 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.702+10T>G		intron_variant	Intron 7 of 20	ENST00000325385.12	NP_689596.4	Q8IYB7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.702+10T>G		intron_variant	Intron 7 of 20	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.00331

AC:

503

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00720

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0166

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00419

AC:

1038

AN:

247796

Hom.:

AF XY:

0.00416

AC XY:

559

AN XY:

134486

show subpopulations

Gnomad AFR exome

AF:

0.000389

Gnomad AMR exome

AF:

0.000853

Gnomad ASJ exome

AF:

0.00627

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.0180

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.00300

GnomAD4 exome

AF:

0.00371

AC:

5424

AN:

1461050

Hom.:

Cov.:

AF XY:

0.00371

AC XY:

2698

AN XY:

726796

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000829

Gnomad4 ASJ exome

AF:

0.00616

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.0196

Gnomad4 NFE exome

AF:

0.00331

Gnomad4 OTH exome

AF:

0.00351

GnomAD4 genome

AF:

0.00330

AC:

503

AN:

152242

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00720

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.0166

Gnomad4 NFE

AF:

0.00345

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00227

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000532

AC:

ESP6500EA

AF:

0.00317

AC:

ExAC

AF:

0.00387

AC:

467

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00367

EpiControl

AF:

0.00304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DIS3L2: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Perlman syndrome

Benign:2

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

- -

not specified

Benign:1

Oct 11, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.8

DANN

Benign

0.95

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.059

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.17

REVEL

Benign

0.0080

Sift

Pathogenic

0.0

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.36

MVP

0.043

ClinPred

0.0087

GERP RS

-3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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