2-232263351-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_152383.5(DIS3L2):​c.1570G>T​(p.Glu524*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

DIS3L2
NM_152383.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.88
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-232263351-G-T is Pathogenic according to our data. Variant chr2-232263351-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1376575.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIS3L2NM_152383.5 linkc.1570G>T p.Glu524* stop_gained Exon 13 of 21 ENST00000325385.12 NP_689596.4 Q8IYB7-1
DIS3L2NM_001257281.2 linkc.1570G>T p.Glu524* stop_gained Exon 13 of 14 NP_001244210.1 Q8IYB7-3
DIS3L2NR_046476.2 linkn.1716G>T non_coding_transcript_exon_variant Exon 13 of 21
DIS3L2NR_046477.2 linkn.1692G>T non_coding_transcript_exon_variant Exon 12 of 19

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIS3L2ENST00000325385.12 linkc.1570G>T p.Glu524* stop_gained Exon 13 of 21 5 NM_152383.5 ENSP00000315569.7 Q8IYB7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Perlman syndrome Pathogenic:1
May 15, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1376575). This sequence change creates a premature translational stop signal (p.Glu524*) in the DIS3L2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DIS3L2 are known to be pathogenic (PMID: 22306653, 28328139). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
43
DANN
Uncertain
1.0
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.95
D
Vest4
0.80
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233128061; API