rs1553610371

chr2-232136567-CCT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152383.5(DIS3L2):c.799_800del(p.Leu267ValfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.14

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 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 2-232136567-CCT-C is Pathogenic according to our data. Variant chr2-232136567-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 463129.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.799_800del	p.Leu267ValfsTer10	frameshift_variant	8/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.799_800del	p.Leu267ValfsTer10	frameshift_variant	8/14
DIS3L2	NR_046476.2	n.945_946del		non_coding_transcript_exon_variant	8/21
DIS3L2	NR_046477.2	n.1072+5625_1072+5626del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.799_800del	p.Leu267ValfsTer10	frameshift_variant	8/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461794 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 02, 2018

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu267Valfs*10) in the DIS3L2 gene. It is expected to result in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with DIS3L2-related disease. ClinVar contains an entry for this variant (Variation ID: 463129). Loss-of-function variants in DIS3L2 are known to be pathogenic (PMID: 22306653). For these reasons, this variant has been classified as Pathogenic. -

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: rs1553610371; hg19: chr2-233001277;