chr2-232329995-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000325385.12(DIS3L2):c.1922A>G(p.Asn641Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000809 in 1,606,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N641D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DIS3L2
ENST00000325385.12 missense, splice_region

Scores

Splicing: ADA: 0.8726

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.087634474).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000325385.12. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIS3L2	NM_152383.5	MANE Select	c.1922A>G	p.Asn641Ser	missense splice_region	Exon 15 of 21	NP_689596.4
DIS3L2	NR_046476.2		n.1995A>G		splice_region non_coding_transcript_exon	Exon 15 of 21
DIS3L2	NR_046477.2		n.1974A>G		splice_region non_coding_transcript_exon	Exon 14 of 19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1922A>G	p.Asn641Ser	missense splice_region	Exon 15 of 21	ENSP00000315569.7
DIS3L2	ENST00000390005.9	TSL:1	n.1849A>G		splice_region non_coding_transcript_exon	Exon 15 of 21	ENSP00000374655.5
DIS3L2	ENST00000445090.5	TSL:1	n.*1078A>G		splice_region non_coding_transcript_exon	Exon 14 of 19	ENSP00000388999.1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000123

AC:

AN:

242968

AF XY:

0.0000227

show subpopulations

Gnomad AFR exome

AF:

0.0000656

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000550

AC:

AN:

1454090

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722618

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33260

American (AMR)

AF:

0.00

AC:

AN:

44174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25908

East Asian (EAS)

AF:

0.00

AC:

AN:

39270

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52634

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107408

Other (OTH)

AF:

0.0000167

AC:

AN:

60044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.039

Eigen

Benign

-0.18

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.0073

MetaRNN

Benign

0.088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.68

PhyloP100

6.8

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.56

REVEL

Benign

0.056

Sift

Benign

0.82

Sift4G

Benign

1.0

Polyphen

0.0040

Vest4

0.36

MVP

0.043

MPC

0.19

ClinPred

0.085

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.11

gMVP

0.49

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.87

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.13

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over