2-232334455-G-T

Variant names:

• chr2-232334455-G-T
• NM_152383.5:c.2245G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152383.5(DIS3L2):​c.2245G>T​(p.Val749Leu) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2245G>T	p.Val749Leu	missense_variant	Exon 18 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-8890G>T		intron_variant	Intron 13 of 13		NP_001244210.1
DIS3L2	NR_046476.2	n.2318G>T		non_coding_transcript_exon_variant	Exon 18 of 21
DIS3L2	NR_046477.2	n.2297G>T		non_coding_transcript_exon_variant	Exon 17 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2245G>T	p.Val749Leu	missense_variant	Exon 18 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Aug 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 749 of the DIS3L2 protein (p.Val749Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	0.036
Eigen_PC	Benign	-0.015
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;.
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.23
Sift	Benign	0.055	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.90	P;P
Vest4		0.79
MutPred		0.48		Loss of ubiquitination at K747 (P = 0.0779);Loss of ubiquitination at K747 (P = 0.0779);
MVP		0.14
MPC		0.78
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.16
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233199165;