rs72998118

chr2-232263269-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152383.5(DIS3L2):c.1488T>C(p.His496=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,614,224 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 32)
  • Exomes 𝑓: 0.015 (230 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.53

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=-0.78).
• BP6: Variant 2-232263269-T-C is Benign according to our data. Variant chr2-232263269-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 241962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232263269-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1821/152336) while in subpopulation NFE AF= 0.0176 (1196/68028). AF 95% confidence interval is 0.0168. There are 17 homozygotes in gnomad4. There are 905 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.1488T>C	p.His496=	synonymous_variant	13/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1488T>C	p.His496=	synonymous_variant	13/14
DIS3L2	NR_046476.2	n.1634T>C		non_coding_transcript_exon_variant	13/21
DIS3L2	NR_046477.2	n.1610T>C		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1488T>C	p.His496=	synonymous_variant	13/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1824 AN: 152218 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0279

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0121 AC: 3019 AN: 249452 Hom.: 33 AF XY: 0.0120 AC XY: 1621 AN XY: 135326

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.00542

Gnomad FIN exome AF: 0.0285

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0151 AC: 22117 AN: 1461888 Hom.: 230 Cov.: 31 AF XY: 0.0149 AC XY: 10803 AN XY: 727244

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00445

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.00232

Gnomad4 SAS exome AF: 0.00568

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0120 AC: 1821 AN: 152336 Hom.: 17 Cov.: 32 AF XY: 0.0121 AC XY: 905 AN XY: 74490

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0279

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.0152 Hom.: 17

Bravo AF: 0.00957

Asia WGS AF: 0.00549 AC: 20 AN: 3476

EpiCase AF: 0.0164

EpiControl AF: 0.0147

ClinVar

Significance: Benign/Likely 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	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	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 10, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.21
Dann	Benign	0.61
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: rs72998118; hg19: chr2-233127979;