2-232336601-G-T

Variant names:

• chr2-232336601-G-T
• rs765768186
• NM_152383.5:c.2629G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152383.5(DIS3L2):​c.2629G>T​(p.Gly877Cys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.288

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0650664).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2629G>T	p.Gly877Cys	missense_variant	Exon 21 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-6744G>T		intron_variant	Intron 13 of 13		NP_001244210.1
DIS3L2	NR_046476.2	n.2702G>T		non_coding_transcript_exon_variant	Exon 21 of 21
DIS3L2	NR_046477.2	n.3275G>T		non_coding_transcript_exon_variant	Exon 19 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2629G>T	p.Gly877Cys	missense_variant	Exon 21 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455458 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724280

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: 0.00

Gnomad4 NFE exome AF: 0.00

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

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 877 of the DIS3L2 protein (p.Gly877Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 949353). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	Benign	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.8
DANN	Benign	0.78
DEOGEN2	Benign	0.0078	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.37	T;.
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.10
Sift	Benign	0.051	T;T
Sift4G	Uncertain	0.042	D;D
Polyphen		0.29	B;B
Vest4		0.22
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.18
MPC		0.23
ClinPred		0.16	T
GERP RS		-7.2
Varity_R		0.062
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs765768186; hg19: chr2-233201311;