rs75782436

Variant names:

• chr2-232334397-C-T
• rs75782436
• NM_152383.5:c.2187C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152383.5(DIS3L2):​c.2187C>T​(p.Pro729Pro) 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:6
• Conservation: PhyloP100: -2.02
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• Perlman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.006).
• BP6: Variant 2-232334397-C-T is Benign according to our data. Variant chr2-232334397-C-T is described in ClinVar as Benign. ClinVar VariationId is 334945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.2187C>T	p.Pro729Pro	synonymous	Exon 18 of 21	NP_689596.4
	DIS3L2	NR_046476.2		n.2260C>T		non_coding_transcript_exon	Exon 18 of 21
	DIS3L2	NR_046477.2		n.2239C>T		non_coding_transcript_exon	Exon 17 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2187C>T	p.Pro729Pro	synonymous	Exon 18 of 21	ENSP00000315569.7
	DIS3L2	ENST00000390005.9	TSL:1	n.*254C>T		non_coding_transcript_exon	Exon 18 of 21	ENSP00000374655.5
	DIS3L2	ENST00000445090.5	TSL:1	n.*1343C>T		non_coding_transcript_exon	Exon 17 of 19	ENSP00000388999.1

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

GnomAD2 exomes AF: 0.0308 AC: 7638 AN: 248298 AF XY: 0.0303

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 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

African (AFR) AF: 0.0779 AC: 2608 AN: 33476

American (AMR) AF: 0.0217 AC: 971 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 1273 AN: 26134

East Asian (EAS) AF: 0.00121 AC: 48 AN: 39696

South Asian (SAS) AF: 0.0234 AC: 2020 AN: 86258

European-Finnish (FIN) AF: 0.0371 AC: 1965 AN: 52946

Middle Eastern (MID) AF: 0.0432 AC: 249 AN: 5768

European-Non Finnish (NFE) AF: 0.0301 AC: 33456 AN: 1111954

Other (OTH) AF: 0.0341 AC: 2057 AN: 60376

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

African (AFR) AF: 0.0756 AC: 3142 AN: 41550

American (AMR) AF: 0.0301 AC: 460 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5164

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4824

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0324 AC: 2201 AN: 68010

Other (OTH) AF: 0.0393 AC: 83 AN: 2114

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Perlman syndrome Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.7
DANN	Benign	0.72
PhyloP100		-2.0
PromoterAI		-0.021	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs75782436; hg19: chr2-233199107;