rs17272089

Positions:

• chr2-232210371-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152383.5(DIS3L2):​c.1170C>T​(p.Leu390=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,613,548 control chromosomes in the GnomAD database, including 638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 32)
  • Exomes 𝑓: 0.026 (599 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.681

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-232210371-C-T is Benign according to our data. Variant chr2-232210371-C-T is described in ClinVar as [Benign]. Clinvar id is 334936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232210371-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.681 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0176 (2688/152304) while in subpopulation SAS AF= 0.0447 (215/4810). AF 95% confidence interval is 0.0398. There are 39 homozygotes in gnomad4. There are 1252 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.1170C>T	p.Leu390=	synonymous_variant	10/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1170C>T	p.Leu390=	synonymous_variant	10/14
DIS3L2	NR_046476.2	n.1316C>T		non_coding_transcript_exon_variant	10/21
DIS3L2	NR_046477.2	n.1292C>T		non_coding_transcript_exon_variant	9/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1170C>T	p.Leu390=	synonymous_variant	10/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2687 AN: 152186 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0440

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.0215 AC: 5373 AN: 249530 Hom.: 91 AF XY: 0.0234 AC XY: 3166 AN XY: 135382

Gnomad AFR exome AF: 0.00452

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.0407

Gnomad FIN exome AF: 0.00988

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0243

GnomAD4 exome AF: 0.0258 AC: 37725 AN: 1461244 Hom.: 599 Cov.: 31 AF XY: 0.0264 AC XY: 19169 AN XY: 726942

Gnomad4 AFR exome AF: 0.00442

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0284

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0401

Gnomad4 FIN exome AF: 0.00914

Gnomad4 NFE exome AF: 0.0274

Gnomad4 OTH exome AF: 0.0252

GnomAD4 genome AF: 0.0176 AC: 2688 AN: 152304 Hom.: 39 Cov.: 32 AF XY: 0.0168 AC XY: 1252 AN XY: 74464

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0308

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0447

Gnomad4 FIN AF: 0.00886

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0232 Hom.: 24

Bravo AF: 0.0169

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0286

EpiControl AF: 0.0270

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

Perlman syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.1
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs17272089; hg19: chr2-233075081; COSMIC: COSV56047717;