rs199541622

Positions:

• chr2-232334711-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.2370C>T​(p.Gly790=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,608,166 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (8 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00500

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=-0.27).
• BP6: Variant 2-232334711-C-T is Benign according to our data. Variant chr2-232334711-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 241975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232334711-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.005 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (354/152348) while in subpopulation NFE AF= 0.00388 (264/68030). AF 95% confidence interval is 0.0035. There are 0 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2370C>T	p.Gly790=	synonymous_variant	19/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-8634C>T		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2	n.2443C>T		non_coding_transcript_exon_variant	19/21
DIS3L2	NR_046477.2	n.2422C>T		non_coding_transcript_exon_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2370C>T	p.Gly790=	synonymous_variant	19/21	5	NM_152383.5	ENSP00000315569	P1

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00280 AC: 669 AN: 238674 Hom.: 0 AF XY: 0.00284 AC XY: 369 AN XY: 129906

Gnomad AFR exome AF: 0.000891

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.000346

Gnomad SAS exome AF: 0.000778

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00433 AC: 6301 AN: 1455818 Hom.: 8 Cov.: 33 AF XY: 0.00422 AC XY: 3052 AN XY: 723868

Gnomad4 AFR exome AF: 0.000871

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00520

Gnomad4 OTH exome AF: 0.00314

GnomAD4 genome AF: 0.00232 AC: 354 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74492

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00345 Hom.: 1

Bravo AF: 0.00254

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Perlman syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	DIS3L2: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2021	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199541622; hg19: chr2-233199421;