2-232238565-G-T

Variant names:

• chr2-232238565-G-T
• rs1553539253
• NM_152383.5:c.1237G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152383.5(DIS3L2):​c.1237G>T​(p.Val413Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1237G>T	p.Val413Leu	missense_variant	Exon 11 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1237G>T	p.Val413Leu	missense_variant	Exon 11 of 14		NP_001244210.1
DIS3L2	NR_046476.2	n.1383G>T		non_coding_transcript_exon_variant	Exon 11 of 21
DIS3L2	NR_046477.2	n.1359G>T		non_coding_transcript_exon_variant	Exon 10 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1237G>T	p.Val413Leu	missense_variant	Exon 11 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Jul 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 413 of the DIS3L2 protein (p.Val413Leu). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 650773). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	.;T;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	4.4	H;H;H;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.92
MutPred		0.89		Loss of phosphorylation at Y415 (P = 0.2815);Loss of phosphorylation at Y415 (P = 0.2815);Loss of phosphorylation at Y415 (P = 0.2815);.;
MVP		0.61
MPC		0.82
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553539253; hg19: chr2-233103275;