2-232014961-C-T

Variant names:

• chr2-232014961-C-T
• rs723044
• NM_152383.5:c.34C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152383.5(DIS3L2):​c.34C>T​(p.Pro12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,613,506 control chromosomes in the GnomAD database, including 2,550 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P12T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (958 hom., cov: 32)
  • Exomes 𝑓: 0.034 (1592 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.275
• Publications: 18 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

ENSG00000227033 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.520054E-4).
• BP6: Variant 2-232014961-C-T is Benign according to our data. Variant chr2-232014961-C-T is described in ClinVar as Benign. ClinVar VariationId is 334928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.34C>T	p.Pro12Ser	missense_variant	Exon 2 of 21	ENST00000325385.12	NP_689596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.34C>T	p.Pro12Ser	missense_variant	Exon 2 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes AF: 0.0799 AC: 12145 AN: 152056 Hom.: 957 Cov.: 32

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.0548

Gnomad FIN AF: 0.0341

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0579

GnomAD2 exomes AF: 0.0450 AC: 11214 AN: 248948 AF XY: 0.0430

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0449

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.00162

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0290

Gnomad OTH exome AF: 0.0471

GnomAD4 exome AF: 0.0343 AC: 50120 AN: 1461332 Hom.: 1592 Cov.: 30 AF XY: 0.0345 AC XY: 25097 AN XY: 726952

African (AFR) AF: 0.207 AC: 6927 AN: 33414

American (AMR) AF: 0.0459 AC: 2051 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 1274 AN: 26122

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39694

South Asian (SAS) AF: 0.0531 AC: 4577 AN: 86162

European-Finnish (FIN) AF: 0.0362 AC: 1934 AN: 53370

Middle Eastern (MID) AF: 0.0524 AC: 302 AN: 5768

European-Non Finnish (NFE) AF: 0.0273 AC: 30400 AN: 1111754

Other (OTH) AF: 0.0434 AC: 2618 AN: 60368

GnomAD4 genome AF: 0.0798 AC: 12148 AN: 152174 Hom.: 958 Cov.: 32 AF XY: 0.0783 AC XY: 5826 AN XY: 74422

African (AFR) AF: 0.202 AC: 8364 AN: 41496

American (AMR) AF: 0.0486 AC: 743 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3470

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5180

South Asian (SAS) AF: 0.0541 AC: 260 AN: 4810

European-Finnish (FIN) AF: 0.0341 AC: 362 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0303 AC: 2059 AN: 67998

Other (OTH) AF: 0.0568 AC: 120 AN: 2112

Alfa AF: 0.0423 Hom.: 1224

Bravo AF: 0.0861

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.197 AC: 726

ESP6500EA AF: 0.0290 AC: 237

ExAC AF: 0.0481 AC: 5806

Asia WGS AF: 0.0480 AC: 168 AN: 3478

EpiCase AF: 0.0272

EpiControl AF: 0.0267

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 13, 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.96
DANN	Benign	0.51
DEOGEN2	Benign	0.0026	.;T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.70	T;T;.;T;.
MetaRNN	Benign	0.00095	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.81	L;L;L;.;L
PhyloP100		-0.28
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.030	N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.0	.;B;B;.;B
Vest4		0.031
MPC		0.22
ClinPred		0.00075	T
GERP RS		0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.33
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs723044; hg19: chr2-232879671; COSMIC: COSV107253913; COSMIC: COSV107253913;