chr2-232333905-T-G

Position:

• chr2-232333905-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152383.5(DIS3L2):​c.2076T>G​(p.Asn692Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. N692H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0870

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.2076T>G	p.Asn692Lys	missense_variant	17/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1582-9440T>G		intron_variant
DIS3L2	NR_046476.2	n.2149T>G		non_coding_transcript_exon_variant	17/21
DIS3L2	NR_046477.2	n.2128T>G		non_coding_transcript_exon_variant	16/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2076T>G	p.Asn692Lys	missense_variant	17/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

Invitae

Oct 30, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DIS3L2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 692 of the DIS3L2 protein (p.Asn692Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.97	D;.;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0080	D;D;T
Polyphen		0.88	P;P;.
Vest4		0.96
MutPred		0.88		Gain of methylation at N692 (P = 0.0367);Gain of methylation at N692 (P = 0.0367);.;
MVP		0.21
MPC		0.85
ClinPred		1.0	D
GERP RS		-2.4
Varity_R		0.90
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs767082193; hg19: chr2-233198615;