2-232300109-G-C

Variant names:

• chr2-232300109-G-C
• rs750651562
• NM_152383.5:c.1729G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152383.5(DIS3L2):​c.1729G>C​(p.Glu577Gln) variant causes a missense change. 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. E577D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13
• Publications: 0 publications found

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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=0.37126637).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.1729G>C	p.Glu577Gln	missense	Exon 14 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1581+36747G>C		intron	N/A	NP_001244210.1
	DIS3L2	NR_046476.2		n.1875G>C		non_coding_transcript_exon	Exon 14 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1729G>C	p.Glu577Gln	missense	Exon 14 of 21	ENSP00000315569.7
	DIS3L2	ENST00000390005.9	TSL:1	n.1729G>C		non_coding_transcript_exon	Exon 14 of 21	ENSP00000374655.5
	DIS3L2	ENST00000445090.5	TSL:1	n.*955G>C		non_coding_transcript_exon	Exon 13 of 19	ENSP00000388999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.023	D
Polyphen		0.50	P
Vest4		0.28
MutPred		0.56		Loss of ubiquitination at K580 (P = 0.093)
MVP		0.14
MPC		0.53
ClinPred		0.86	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.50
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs750651562; hg19: chr2-233164819;