2-232333842-G-T

Variant names:

• chr2-232333842-G-T
• NM_152383.5:c.2013G>T

Variant summary

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

The NM_152383.5(DIS3L2):​c.2013G>T​(p.Met671Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.70

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.2013G>T	p.Met671Ile	missense_variant, splice_region_variant	Exon 17 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-9503G>T		intron_variant	Intron 13 of 13		NP_001244210.1
DIS3L2	NR_046476.2	n.2086G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 21
DIS3L2	NR_046477.2	n.2065G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2013G>T	p.Met671Ile	missense_variant, splice_region_variant	Exon 17 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1457958 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 2 AN XY: 725332

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 671 of the DIS3L2 protein (p.Met671Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DIS3L2-related conditions (PMID: 35980532). ClinVar contains an entry for this variant (Variation ID: 1061841). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	0.80
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.31	B;B;.
Vest4		0.85
MutPred		0.61		Loss of helix (P = 0.2271);Loss of helix (P = 0.2271);.;
MVP		0.068
MPC		0.60
ClinPred		0.94	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr2-233198552;