rs1553551874

Variant names:

• chr2-232334719-AGC-A
• rs1553551874
• NM_152383.5:c.2381_2382delGC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_152383.5(DIS3L2):​c.2381_2382delGC​(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). Synonymous variant affecting the same amino acid position (i.e. R794R) has been classified as Likely benign. 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Perlman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 438774.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2381_2382delGC	p.Arg794HisfsTer29	frameshift_variant	Exon 19 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NR_046476.2	n.2454_2455delGC		non_coding_transcript_exon_variant	Exon 19 of 21
DIS3L2	NR_046477.2	n.2433_2434delGC		non_coding_transcript_exon_variant	Exon 18 of 19
DIS3L2	NM_001257281.2	c.1582-8623_1582-8622delGC		intron_variant	Intron 13 of 13		NP_001244210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2381_2382delGC	p.Arg794HisfsTer29	frameshift_variant	Exon 19 of 21	5	NM_152383.5	ENSP00000315569.7

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

Jan 30, 2014

Donald Williams Parsons Laboratory, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9

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

Other links and lift over

dbSNP: rs1553551874; hg19: chr2-233199429;