chr2-232336548-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152383.5(DIS3L2):c.2576G>C(p.Arg859Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,609,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R859G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.83

Publications

1 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06751317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.2576G>C	p.Arg859Pro	missense_variant	Exon 21 of 21	ENST00000325385.12	NP_689596.4	Q8IYB7-1
DIS3L2	NR_046476.2 link	n.2649G>C		non_coding_transcript_exon_variant	Exon 21 of 21
DIS3L2	NR_046477.2 link	n.3222G>C		non_coding_transcript_exon_variant	Exon 19 of 19
DIS3L2	NM_001257281.2 link	c.1582-6797G>C		intron_variant	Intron 13 of 13		NP_001244210.1	Q8IYB7-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.2576G>C	p.Arg859Pro	missense_variant	Exon 21 of 21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

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

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

244788

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000279

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000960

AC:

AN:

1457756

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

725376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000353

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111948

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000580

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:2

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 859 of the DIS3L2 protein (p.Arg859Pro). This variant is present in population databases (rs570999208, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 531944). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2576G>C (p.R859P) alteration is located in exon 21 (coding exon 20) of the DIS3L2 gene. This alteration results from a G to C substitution at nucleotide position 2576, causing the arginine (R) at amino acid position 859 to be replaced by a proline (P). 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

0.17

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.65

T;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.068

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L

PhyloP100

2.8

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.24

Sift

Benign

0.11

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.0010

B;B

Vest4

0.30

MutPred

0.50

Loss of MoRF binding (P = 0.005);Loss of MoRF binding (P = 0.005);

MVP

0.13

MPC

0.34

ClinPred

0.17

GERP RS

3.5

Varity_R

0.16

gMVP

0.70

Mutation Taster

=63/37

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over