rs2697798

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152383.5(DIS3L2):c.2329A>G(p.Ile777Val) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 152,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. I777M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.87

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022104353).

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.2329A>G	p.Ile777Val	missense	Exon 19 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.1582-8675A>G		intron	N/A	NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2		n.2402A>G		non_coding_transcript_exon	Exon 19 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2329A>G	p.Ile777Val	missense	Exon 19 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000390005.9	TSL:1	n.*396A>G		non_coding_transcript_exon	Exon 19 of 21	ENSP00000374655.5	Q8IYB7-2
DIS3L2	ENST00000445090.5	TSL:1	n.*1485A>G		non_coding_transcript_exon	Exon 18 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000218

AC:

AN:

234404

AF XY:

0.000290

show subpopulations

Gnomad AFR exome

AF:

0.000212

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000295

Gnomad FIN exome

AF:

0.0000992

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000185

AC:

262

AN:

1418476

Hom.:

Cov.:

AF XY:

0.000214

AC XY:

151

AN XY:

705340

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000248

AC:

AN:

32214

American (AMR)

AF:

0.000544

AC:

AN:

42298

Ashkenazi Jewish (ASJ)

AF:

0.000275

AC:

AN:

25446

East Asian (EAS)

AF:

0.000338

AC:

AN:

38464

South Asian (SAS)

AF:

0.000387

AC:

AN:

82618

European-Finnish (FIN)

AF:

0.000193

AC:

AN:

51820

Middle Eastern (MID)

AF:

0.00108

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.000134

AC:

145

AN:

1081200

Other (OTH)

AF:

0.000306

AC:

AN:

58852

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.290

Heterozygous variant carriers

112

140

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:

0.000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41546

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000389

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

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:

0.000240

Hom.:

ExAC

AF:

0.00108

AC:

131

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perlman syndrome (5)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.012

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.29

M_CAP

Benign

0.0054

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.5

PhyloP100

4.9

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.54

REVEL

Benign

0.071

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.17

MVP

0.043

MPC

0.18

ClinPred

0.14

GERP RS

3.1

PromoterAI

-0.024

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.028

gMVP

0.24

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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