Genetic Variant DIS3L2:p.Gly638Ala (chr2-232329986-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_152383.5(DIS3L2):c.1913G>C(p.Gly638Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. G638E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.76

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33511317).

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.1913G>C	p.Gly638Ala	missense	Exon 15 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.1582-13359G>C		intron	N/A	NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2		n.1986G>C		non_coding_transcript_exon	Exon 15 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1913G>C	p.Gly638Ala	missense	Exon 15 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000390005.9	TSL:1	n.1840G>C		non_coding_transcript_exon	Exon 15 of 21	ENSP00000374655.5	Q8IYB7-2
DIS3L2	ENST00000445090.5	TSL:1	n.*1069G>C		non_coding_transcript_exon	Exon 14 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

244944

AF XY:

0.00000751

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000902

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

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

0.12

BayesDel_addAF

Benign

0.0047

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

0.042

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.031

MetaRNN

Benign

0.34

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.46

PhyloP100

7.8

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.19

Sift

Benign

0.41

Sift4G

Benign

0.39

Polyphen

0.061

Vest4

0.71

MutPred

0.54

Gain of loop (P = 0.1069)

MVP

0.043

MPC

0.62

ClinPred

0.85

GERP RS

5.3

Varity_R

0.42

gMVP

0.69

Mutation Taster

=8/92

disease causing

(source)

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

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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