2-232336618-A-G

Position:

• chr2-232336618-A-G

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.2646A>G​(p.Ser882Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,603,266 control chromosomes in the GnomAD database, including 13,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1713 hom., cov: 32)
  • Exomes 𝑓: 0.10 (11368 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.256

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 2-232336618-A-G is Benign according to our data. Variant chr2-232336618-A-G is described in ClinVar as [Benign]. Clinvar id is 262631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.256 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2646A>G	p.Ser882Ser	synonymous_variant	21/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-6727A>G		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2	n.2719A>G		non_coding_transcript_exon_variant	21/21
DIS3L2	NR_046477.2	n.3292A>G		non_coding_transcript_exon_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2646A>G	p.Ser882Ser	synonymous_variant	21/21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19115 AN: 151878 Hom.: 1700 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.0801

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.143 AC: 32887 AN: 230524 Hom.: 3746 AF XY: 0.132 AC XY: 16703 AN XY: 126834

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.455

Gnomad SAS exome AF: 0.0745

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0873

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.101 AC: 146236 AN: 1451268 Hom.: 11368 Cov.: 32 AF XY: 0.0995 AC XY: 71861 AN XY: 721996

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.0871

Gnomad4 EAS exome AF: 0.481

Gnomad4 SAS exome AF: 0.0778

Gnomad4 FIN exome AF: 0.0896

Gnomad4 NFE exome AF: 0.0815

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.126 AC: 19152 AN: 151998 Hom.: 1713 Cov.: 32 AF XY: 0.127 AC XY: 9437 AN XY: 74294

Gnomad4 AFR AF: 0.153

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.0842

Gnomad4 EAS AF: 0.458

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.0801

Gnomad4 NFE AF: 0.0849

Gnomad4 OTH AF: 0.144

Alfa AF: 0.0899 Hom.: 861

Bravo AF: 0.140

Asia WGS AF: 0.222 AC: 771 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Perlman syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.0
DANN	Benign	0.52

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: rs3811578; hg19: chr2-233201328; COSMIC: COSV56053495; COSMIC: COSV56053495;