chr2-232343480-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001257281.2(DIS3L2):​c.1717C>T​(p.Arg573*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000148 in 1,555,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

DIS3L2
NM_001257281.2 stop_gained

Scores

2
1
4

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.27
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]
NRBF2P6 (HGNC:54797): (NRBF2 pseudogene 6)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0524 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIS3L2NM_001257281.2 linkc.1717C>T p.Arg573* stop_gained Exon 14 of 14 NP_001244210.1 Q8IYB7-3
NRBF2P6 n.232343480C>T intragenic_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIS3L2ENST00000273009.10 linkc.1717C>T p.Arg573* stop_gained Exon 14 of 14 2 ENSP00000273009.6 Q8IYB7-3
NRBF2P6ENST00000513620.1 linkn.365C>T non_coding_transcript_exon_variant Exon 1 of 1 6

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000494
AC:
8
AN:
161984
Hom.:
0
AF XY:
0.0000349
AC XY:
3
AN XY:
86038
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000317
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000150
AC:
21
AN:
1403632
Hom.:
0
Cov.:
30
AF XY:
0.0000115
AC XY:
8
AN XY:
692754
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000249
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000835
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000647
Gnomad4 OTH exome
AF:
0.0000343
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000179
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

DIS3L2-related disorder Uncertain:1
May 22, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The DIS3L2 c.1717C>T variant is predicted to result in premature protein termination (p.Arg573*). To our knowledge, this variant has not been reported in the literature. This variant is post coding on the main transcript NM_152383:c.*6850C>T and is not expected to impact protein function. This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.37
CADD
Pathogenic
34
DANN
Uncertain
0.97
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.086
N
Vest4
0.089
GERP RS
0.12

Splicing

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.

Other links and lift over

dbSNP: rs776084035; hg19: chr2-233208190; API