2-232130712-C-T

Position:

• chr2-232130712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152383.5(DIS3L2):​c.695C>T​(p.Ser232Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.62

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20640478).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.695C>T	p.Ser232Leu	missense_variant	7/21	ENST00000325385.12	NP_689596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.695C>T	p.Ser232Leu	missense_variant	7/21	5	NM_152383.5	ENSP00000315569	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248878 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135024

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461556 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.00000828 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.695C>T (p.S232L) alteration is located in exon 7 (coding exon 6) of the DIS3L2 gene. This alteration results from a C to T substitution at nucleotide position 695, causing the serine (S) at amino acid position 232 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Perlman syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 232 of the DIS3L2 protein (p.Ser232Leu). This variant is present in population databases (rs747734015, gnomAD 0.006%). 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: 576703). 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 not expected to disrupt DIS3L2 protein function with a negative predictive value of 80%. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 20, 2023

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	.;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D;D;.;.
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	A;D;D;D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Benign	0.087	T;T;D;T
Polyphen		0.11, 0.97	.;B;D;B
Vest4		0.38
MutPred		0.37		Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);Loss of disorder (P = 0.0238);
MVP		0.043
MPC		0.24
ClinPred		0.90	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.63

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: rs747734015; hg19: chr2-232995422;