2-232163461-A-G

Position:

• chr2-232163461-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152383.5(DIS3L2):​c.953A>G​(p.Gln318Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. Q318H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0836612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.953A>G	p.Gln318Arg	missense_variant, splice_region_variant	9/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.953A>G	p.Gln318Arg	missense_variant, splice_region_variant	9/14
DIS3L2	NR_046476.2	n.1099A>G		splice_region_variant, non_coding_transcript_exon_variant	9/21
DIS3L2	NR_046477.2	n.1075A>G		splice_region_variant, non_coding_transcript_exon_variant	8/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.953A>G	p.Gln318Arg	missense_variant, splice_region_variant	9/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2022

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 318 of the DIS3L2 protein (p.Gln318Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410773). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0096	.;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.75	T;T;.
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.67	N;N;N
MutationTaster	Benign	0.58	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.14
MutPred		0.40		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.043
MPC		0.24
ClinPred		0.61	D
GERP RS		5.4
Varity_R		0.087
gMVP		0.58

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: rs1060503038; hg19: chr2-233028171;