2-232336580-A-G

Position:

chr2-232336580-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152383.5(DIS3L2):c.2608A>G(p.Lys870Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,608,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.101

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021950454).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DIS3L2	NM_152383.5 linkuse as main transcript	c.2608A>G	p.Lys870Glu	missense_variant	21/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2 linkuse as main transcript	c.1582-6765A>G		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2 linkuse as main transcript	n.2681A>G		non_coding_transcript_exon_variant	21/21
DIS3L2	NR_046477.2 linkuse as main transcript	n.3254A>G		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.2608A>G	p.Lys870Glu	missense_variant	21/21	5	NM_152383.5	ENSP00000315569	P1	Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.0000922

AC:

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000115

AC:

AN:

243444

Hom.:

AF XY:

0.000150

AC XY:

AN XY:

133172

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000335

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000570

AC:

AN:

1456858

Hom.:

Cov.:

AF XY:

0.0000717

AC XY:

AN XY:

724954

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000206

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000922

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74212

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000583

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000849

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 870 of the DIS3L2 protein (p.Lys870Glu). This variant is present in population databases (rs775252407, 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: 463111). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 15, 2022

DNA sequence analysis of the DIS3L2 gene demonstrated a sequence change, c.2608A>G, in exon 21 that results in an amino acid change, p.Lys870Glu. This sequence change does not appear to have been previously described in individuals with DIS3L2-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.012% in the overall population (dbSNP rs775252407). The p.Lys870Glu change affects a poorly conserved amino acid residue located in a domain of the DIS3L2 protein that is not known to be functional. The p.Lys870Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Lys870Glu change remains unknown at this time. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.2608A>G (p.K870E) alteration is located in exon 21 (coding exon 20) of the DIS3L2 gene. This alteration results from a A to G substitution at nucleotide position 2608, causing the lysine (K) at amino acid position 870 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.3

DANN

Benign

0.31

DEOGEN2

Benign

0.0033

T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00043

LIST_S2

Benign

0.20

T;.

M_CAP

Benign

0.00093

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.040

Sift

Benign

1.0

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.0

B;B

Vest4

0.24

MutPred

0.27

Loss of ubiquitination at K870 (P = 0.0051);Loss of ubiquitination at K870 (P = 0.0051);

MVP

0.14

MPC

0.30

ClinPred

0.0063

GERP RS

0.34

Varity_R

0.044

gMVP

0.11

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