rs1060503038

Positions:

• chr2-232163461-A-C
• chr2-232163461-A-G

Variant summary

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

The NM_152383.5(DIS3L2):​c.953A>C​(p.Gln318Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.953A>C	p.Gln318Pro	missense_variant, splice_region_variant	9/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.953A>C	p.Gln318Pro	missense_variant, splice_region_variant	9/14
DIS3L2	NR_046476.2	n.1099A>C		splice_region_variant, non_coding_transcript_exon_variant	9/21
DIS3L2	NR_046477.2	n.1075A>C		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>C	p.Gln318Pro	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

Sep 15, 2021

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. 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. This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with proline at codon 318 of the DIS3L2 protein (p.Gln318Pro). The glutamine residue is weakly conserved and there is a moderate physicochemical difference between glutamine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	.;T;T
Eigen	Benign	0.032
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.019	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		0.096	.;B;B
Vest4		0.64
MutPred		0.52		Gain of glycosylation at Q318 (P = 0.0505);Gain of glycosylation at Q318 (P = 0.0505);Gain of glycosylation at Q318 (P = 0.0505);
MVP		0.043
MPC		0.34
ClinPred		0.79	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-233028171;