chr2-232334453-GCGTGC-ACATGA

Position:

• chr2-232334453-GCGTGC-ACATGA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152383.5(DIS3L2):​c.2243_2248delGCGTGCinsACATGA​(p.ArgValGln748HisMetLys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2243_2248delGCGTGCinsACATGA	p.ArgValGln748HisMetLys	missense_variant		ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-8892_1582-8887delGCGTGCinsACATGA		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2	n.2316_2321delGCGTGCinsACATGA		non_coding_transcript_exon_variant	18/21
DIS3L2	NR_046477.2	n.2295_2300delGCGTGCinsACATGA		non_coding_transcript_exon_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2243_2248delGCGTGCinsACATGA	p.ArgValGln748HisMetLys	missense_variant		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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 05, 2017

This sequence change deletes 6 nucleotides and inserts 6 nucleotides in exon 18 of the DIS3L2 mRNA (c.2243_2248delinsACATGA). This results in the deletion of 3 amino acids and insertion of 3 amino acids to the DIS3L2 protein (p.Arg748_Gln750delinsHisMetLys), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a DIS3L2-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. In summary, this variant has uncertain impact on DIS3L2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553551794; hg19: chr2-233199163;