chr2-232263247-G-A

Position:

• chr2-232263247-G-A

Variant summary

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

The NM_152383.5(DIS3L2):​c.1466G>A​(p.Cys489Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.66

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, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1466G>A	p.Cys489Tyr	missense_variant	13/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1466G>A	p.Cys489Tyr	missense_variant	13/14		NP_001244210.1
DIS3L2	NR_046476.2	n.1612G>A		non_coding_transcript_exon_variant	13/21
DIS3L2	NR_046477.2	n.1588G>A		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1466G>A	p.Cys489Tyr	missense_variant	13/21	5	NM_152383.5	ENSP00000315569	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000454 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2022	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DIS3L2 protein function. ClinVar contains an entry for this variant (Variation ID: 31125). This missense change has been observed in individual(s) with Perlman syndrome (PMID: 22306653). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 489 of the DIS3L2 protein (p.Cys489Tyr). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 05, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.7	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0060	D;T;T;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.98	.;D;D;.
Vest4		0.95
MutPred		0.39		Gain of MoRF binding (P = 0.073);Gain of MoRF binding (P = 0.073);Gain of MoRF binding (P = 0.073);.;
MVP		0.66
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.75

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: rs387907116; hg19: chr2-233127957;