Genetic Variant DIS3L2:p.Thr221Ile (chr2-232130679-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152383.5(DIS3L2):c.662C>T(p.Thr221Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T221R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.11

Publications

0 publications found

Variant links:

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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

DIS3L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09069246).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	NM_152383.5	MANE Select	c.662C>T	p.Thr221Ile	missense	Exon 7 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.662C>T	p.Thr221Ile	missense	Exon 7 of 14	NP_001244210.1	Q8IYB7-3
DIS3L2	NM_001257282.2		c.662C>T	p.Thr221Ile	missense	Exon 7 of 7	NP_001244211.1	Q8IYB7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.662C>T	p.Thr221Ile	missense	Exon 7 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000409401.7	TSL:1	c.662C>T	p.Thr221Ile	missense	Exon 7 of 7	ENSP00000386594.3	Q8IYB7-4
DIS3L2	ENST00000390005.9	TSL:1	n.662C>T		non_coding_transcript_exon	Exon 7 of 21	ENSP00000374655.5	Q8IYB7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461672

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111896

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.53

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

PhyloP100

4.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.6

REVEL

Benign

0.053

Sift

Benign

0.23

Sift4G

Benign

0.20

Polyphen

0.044

Vest4

0.14

MutPred

0.30

Gain of sheet (P = 0.0477)

MVP

0.093

MPC

0.26

ClinPred

0.63

GERP RS

4.4

Varity_R

0.042

gMVP

0.26

Mutation Taster

=37/163

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over