NM_152383.5:c.2243_2248delGCGTGCinsACATGA

Variant names:

• chr2-232334453-GCGTGC-ACATGA
• rs1553551794
• NM_152383.5:c.2243_2248delGCGTGCinsACATGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. 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. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R748R) has been classified as Benign.

• 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
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.2243_2248delGCGTGCinsACATGA	p.ArgValGln748HisMetLys	missense	N/A	NP_689596.4
	DIS3L2	NR_046476.2		n.2316_2321delGCGTGCinsACATGA		non_coding_transcript_exon	Exon 18 of 21
	DIS3L2	NR_046477.2		n.2295_2300delGCGTGCinsACATGA		non_coding_transcript_exon	Exon 17 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2243_2248delGCGTGCinsACATGA	p.ArgValGln748HisMetLys	missense	N/A	ENSP00000315569.7
	DIS3L2	ENST00000390005.9	TSL:1	n.*310_*315delGCGTGCinsACATGA		non_coding_transcript_exon	Exon 18 of 21	ENSP00000374655.5
	DIS3L2	ENST00000445090.5	TSL:1	n.*1399_*1404delGCGTGCinsACATGA		non_coding_transcript_exon	Exon 17 of 19	ENSP00000388999.1

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

Jun 05, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

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

Other links and lift over

dbSNP: rs1553551794; hg19: chr2-233199163;