rs113330536

Variant names:

• chr2-232330735-C-G
• NM_152383.5:c.1969C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-232330735-C-G
• chr2-232330735-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152383.5(DIS3L2):​c.1969C>G​(p.Arg657Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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: 2.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26541758).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1969C>G	p.Arg657Gly	missense_variant	Exon 16 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-12610C>G		intron_variant	Intron 13 of 13		NP_001244210.1
DIS3L2	NR_046476.2	n.2042C>G		non_coding_transcript_exon_variant	Exon 16 of 21
DIS3L2	NR_046477.2	n.2021C>G		non_coding_transcript_exon_variant	Exon 15 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1969C>G	p.Arg657Gly	missense_variant	Exon 16 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Sep 13, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DIS3L2 protein function. This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 657 of the DIS3L2 protein (p.Arg657Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.032
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.22
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.34	T;T;T
Polyphen		0.021	B;B;.
Vest4		0.78
MutPred		0.62		Loss of stability (P = 0.0236);Loss of stability (P = 0.0236);.;
MVP		0.043
MPC		0.73
ClinPred		0.98	D
GERP RS		3.0
Varity_R		0.65
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr2-233195445;