rs1553551874

Positions:

• chr2-232334719-AGC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_152383.5(DIS3L2):​c.2381_2382del​(p.Arg794HisfsTer29) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 2-232334719-AGC-A is Pathogenic according to our data. Variant chr2-232334719-AGC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 438774.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2381_2382del	p.Arg794HisfsTer29	frameshift_variant	19/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-8623_1582-8622del		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2	n.2454_2455del		non_coding_transcript_exon_variant	19/21
DIS3L2	NR_046477.2	n.2433_2434del		non_coding_transcript_exon_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2381_2382del	p.Arg794HisfsTer29	frameshift_variant	19/21	5	NM_152383.5	ENSP00000315569	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Nephroblastoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Donald Williams Parsons Laboratory, Baylor College of Medicine

Jan 30, 2014

This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213). It was found once in our study paternally inherited in a 5-year-old female with Wilms tumor; the tumor showed LOH in this region. The patient also had paternally inherited heterozygous loss-of-function variants in CHEK2 and FANCC. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1553551874; hg19: chr2-233199429;