chr2-232329995-A-G

Position:

chr2-232329995-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152383.5(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. 15/23 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 (★).

Frequency

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

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense, splice_region

Scores

Splicing: ADA: 0.8726

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.76

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:

DIS3L2 (HGNC:):

DIS3L2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5 linkuse as main transcript	c.1922A>G	p.Asn641Ser	missense_variant, splice_region_variant	15/21	ENST00000325385.12	NP_689596.4	Q8IYB7-1
DIS3L2	NM_001257281.2 linkuse as main transcript	c.1582-13350A>G		intron_variant			NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2 linkuse as main transcript	n.1995A>G		splice_region_variant, non_coding_transcript_exon_variant	15/21
DIS3L2	NR_046477.2 linkuse as main transcript	n.1974A>G		splice_region_variant, non_coding_transcript_exon_variant	14/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.1922A>G	p.Asn641Ser	missense_variant, splice_region_variant	15/21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

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

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

242968

Hom.:

AF XY:

0.0000227

AC XY:

AN XY:

132150

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 SAS exome

AF:

0.0000669

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

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000350

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2023

This variant is present in population databases (rs769948942, gnomAD 0.007%). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 463082). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 641 of the DIS3L2 protein (p.Asn641Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.039

T;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;.;D

M_CAP

Benign

0.0073

MetaRNN

Benign

0.088

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.68

N;N;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.56

N;N;N

REVEL

Benign

0.056

Sift

Benign

0.82

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0040

B;B;.

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

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

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