rs186865544

Positions:

• chr2-232263228-C-G
• chr2-232263228-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_152383.5(DIS3L2):​c.1447C>G​(p.Arg483Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,614,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3 O:1
• Conservation: PhyloP100: 3.92

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]

DIS3L2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18036667).
• BP6: Variant 2-232263228-C-G is Benign according to our data. Variant chr2-232263228-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241961.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=7, not_provided=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000841 (128/152274) while in subpopulation NFE AF= 0.00156 (106/68026). AF 95% confidence interval is 0.00132. There are 0 homozygotes in gnomad4. There are 52 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1447C>G	p.Arg483Gly	missense_variant	13/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1447C>G	p.Arg483Gly	missense_variant	13/14		NP_001244210.1
DIS3L2	NR_046476.2	n.1593C>G		non_coding_transcript_exon_variant	13/21
DIS3L2	NR_046477.2	n.1569C>G		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1447C>G	p.Arg483Gly	missense_variant	13/21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000750 AC: 187 AN: 249354 Hom.: 0 AF XY: 0.000695 AC XY: 94 AN XY: 135272

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00118 AC: 1720 AN: 1461872 Hom.: 2 Cov.: 31 AF XY: 0.00116 AC XY: 842 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74452

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.000805

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.000678 AC: 82

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Perlman syndrome Uncertain:5 Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 01, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine (exon 13). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (210 Heterozygous, 0 Homozygous). (P) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (highest allele count: 3631 Heterozygous, 66 Homozygous). (N) 0502 - Missense variant with conflicting in silico predictions with low conservation. (N) 0600 - Variant is located in the RNB domain (NCBI conserved domain). (N) 0710 - Comparable variants have some previous evidence for being benign (ClinVar). (B) 0804 - Variant has previously been described as variant of uncertain significance in two independent cases with consistent phenotype (ClinVar). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant in the literature. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 12-04-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 10, 2022	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23613427, 22306653, 24909261, 30256826) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	DIS3L2: BP4 -

DIS3L2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;T;T;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;D
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.18	T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	4.3	H;H;H;.
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.0	D;D;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.86
MVP		0.56
MPC		0.93
ClinPred		0.70	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.84

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: rs186865544; hg19: chr2-233127938;