2-232014961-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152383.5(DIS3L2):c.34C>T(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,506 control chromosomes in the GnomAD database, including 2,550 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.080 ( 958 hom., cov: 32)

Exomes 𝑓: 0.034 ( 1592 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.275

Publications

18 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

DIS3L2 links:

ENSG00000227033 (HGNC:):

ENSG00000227033 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.520054E-4).

BP6

Variant 2-232014961-C-T is Benign according to our data. Variant chr2-232014961-C-T is described in ClinVar as Benign. ClinVar VariationId is 334928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	NM_152383.5	MANE Select	c.34C>T	p.Pro12Ser	missense	Exon 2 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.34C>T	p.Pro12Ser	missense	Exon 2 of 14	NP_001244210.1	Q8IYB7-3
DIS3L2	NM_001257282.2		c.34C>T	p.Pro12Ser	missense	Exon 2 of 7	NP_001244211.1	Q8IYB7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.34C>T	p.Pro12Ser	missense	Exon 2 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000409401.7	TSL:1	c.34C>T	p.Pro12Ser	missense	Exon 2 of 7	ENSP00000386594.3	Q8IYB7-4
DIS3L2	ENST00000390005.9	TSL:1	n.34C>T		non_coding_transcript_exon	Exon 2 of 21	ENSP00000374655.5	Q8IYB7-2

Frequencies

GnomAD3 genomes

AF:

0.0799

AC:

12145

AN:

152056

Hom.:

957

Cov.:

show subpopulations

Gnomad AFR

AF:

0.202

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.0487

Gnomad ASJ

AF:

0.0481

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0548

Gnomad FIN

AF:

0.0341

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0579

GnomAD2 exomes

AF:

0.0450

AC:

11214

AN:

248948

AF XY:

0.0430

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.0449

Gnomad ASJ exome

AF:

0.0472

Gnomad EAS exome

AF:

0.00162

Gnomad FIN exome

AF:

0.0373

Gnomad NFE exome

AF:

0.0290

Gnomad OTH exome

AF:

0.0471

GnomAD4 exome

AF:

0.0343

AC:

50120

AN:

1461332

Hom.:

1592

Cov.:

AF XY:

0.0345

AC XY:

25097

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.207

AC:

6927

AN:

33414

American (AMR)

AF:

0.0459

AC:

2051

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0488

AC:

1274

AN:

26122

East Asian (EAS)

AF:

0.000932

AC:

AN:

39694

South Asian (SAS)

AF:

0.0531

AC:

4577

AN:

86162

European-Finnish (FIN)

AF:

0.0362

AC:

1934

AN:

53370

Middle Eastern (MID)

AF:

0.0524

AC:

302

AN:

5768

European-Non Finnish (NFE)

AF:

0.0273

AC:

30400

AN:

1111754

Other (OTH)

AF:

0.0434

AC:

2618

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

2447

4894

7340

9787

12234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1216

2432

3648

4864

6080

<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:

0.0798

AC:

12148

AN:

152174

Hom.:

958

Cov.:

AF XY:

0.0783

AC XY:

5826

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.202

AC:

8364

AN:

41496

American (AMR)

AF:

0.0486

AC:

743

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0481

AC:

167

AN:

3470

East Asian (EAS)

AF:

0.00193

AC:

AN:

5180

South Asian (SAS)

AF:

0.0541

AC:

260

AN:

4810

European-Finnish (FIN)

AF:

0.0341

AC:

362

AN:

10608

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0303

AC:

2059

AN:

67998

Other (OTH)

AF:

0.0568

AC:

120

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

529

1058

1587

2116

2645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.0423

Hom.:

1224

Bravo

AF:

0.0861

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0283

AC:

109

ESP6500AA

AF:

0.197

AC:

726

ESP6500EA

AF:

0.0290

AC:

237

ExAC

AF:

0.0481

AC:

5806

Asia WGS

AF:

0.0480

AC:

168

AN:

3478

EpiCase

AF:

0.0272

EpiControl

AF:

0.0267

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Perlman syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.96

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0026

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.70

MetaRNN

Benign

0.00095

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.81

PhyloP100

-0.28

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.030

REVEL

Benign

0.064

Sift

Benign

0.27

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.031

MPC

0.22

ClinPred

0.00075

GERP RS

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.33

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over