2-232335828-C-T

Position:

chr2-232335828-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_152383.5(DIS3L2):c.2450C>T(p.Thr817Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000451 in 1,550,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T817R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17309979).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000458 (64/1398562) while in subpopulation MID AF= 0.000357 (2/5610). AF 95% confidence interval is 0.000198. There are 0 homozygotes in gnomad4_exome. There are 36 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DIS3L2	NM_152383.5 linkuse as main transcript	c.2450C>T	p.Thr817Met	missense_variant	20/21	ENST00000325385.12
DIS3L2	NM_001257281.2 linkuse as main transcript	c.1582-7517C>T		intron_variant
DIS3L2	NR_046476.2 linkuse as main transcript	n.2523C>T		non_coding_transcript_exon_variant	20/21
DIS3L2	NR_046477.2 linkuse as main transcript	n.2502C>T		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.2450C>T	p.Thr817Met	missense_variant	20/21	5	NM_152383.5	P1	Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000646

AC:

AN:

154720

Hom.:

AF XY:

0.0000732

AC XY:

AN XY:

81938

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000166

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1398562

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

689806

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000290

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000130

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 24, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 817 of the DIS3L2 protein (p.Thr817Met). This variant is present in population databases (rs376816858, gnomAD 0.04%). 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: 410769). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.81

T;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.8

D;D;D

REVEL

Benign

0.11

Sift

Uncertain

0.012

D;D;D

Sift4G

Uncertain

0.030

D;D;D

Polyphen

0.96

D;D;.

Vest4

0.12

MutPred

0.34

Loss of phosphorylation at T817 (P = 0.0618);Loss of phosphorylation at T817 (P = 0.0618);.;

MVP

0.25

MPC

0.28

ClinPred

0.66

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.55

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

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