rs75782436

chr2-232334397-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152383.5(DIS3L2):c.2187C>T(p.Pro729=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 1,613,586 control chromosomes in the GnomAD database, including 994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (188 hom., cov: 33)
  • Exomes 𝑓: 0.031 (806 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.02

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-232334397-C-T is Benign according to our data. Variant chr2-232334397-C-T is described in ClinVar as [Benign]. Clinvar id is 334945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232334397-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.2187C>T	p.Pro729=	synonymous_variant	18/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1582-8948C>T		intron_variant
DIS3L2	NR_046476.2	n.2260C>T		non_coding_transcript_exon_variant	18/21
DIS3L2	NR_046477.2	n.2239C>T		non_coding_transcript_exon_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2187C>T	p.Pro729=	synonymous_variant	18/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6571 AN: 152144 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0324

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0308 AC: 7638 AN: 248298 Hom.: 173 AF XY: 0.0303 AC XY: 4097 AN XY: 135038

Gnomad AFR exome AF: 0.0765

Gnomad AMR exome AF: 0.0214

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.00178

Gnomad SAS exome AF: 0.0235

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0396

GnomAD4 exome AF: 0.0306 AC: 44647 AN: 1461324 Hom.: 806 Cov.: 33 AF XY: 0.0306 AC XY: 22219 AN XY: 726962

Gnomad4 AFR exome AF: 0.0779

Gnomad4 AMR exome AF: 0.0217

Gnomad4 ASJ exome AF: 0.0487

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.0371

Gnomad4 NFE exome AF: 0.0301

Gnomad4 OTH exome AF: 0.0341

GnomAD4 genome AF: 0.0432 AC: 6583 AN: 152262 Hom.: 188 Cov.: 33 AF XY: 0.0424 AC XY: 3160 AN XY: 74446

Gnomad4 AFR AF: 0.0756

Gnomad4 AMR AF: 0.0301

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0197

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0324

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0395 Hom.: 66

Bravo AF: 0.0446

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.0291

EpiControl AF: 0.0277

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Perlman syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.7
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs75782436; hg19: chr2-233199107;