rs1060503029

Variant names:

• chr2-232087662-T-C
• rs1060503029
• NM_152383.5:c.542T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152383.5(DIS3L2):​c.542T>C​(p.Ile181Thr) 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 benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.227
• 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033980638).

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.542T>C	p.Ile181Thr	missense	Exon 6 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.542T>C	p.Ile181Thr	missense	Exon 6 of 14	NP_001244210.1	Q8IYB7-3
	DIS3L2	NM_001257282.2		c.542T>C	p.Ile181Thr	missense	Exon 6 of 7	NP_001244211.1	Q8IYB7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.542T>C	p.Ile181Thr	missense	Exon 6 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000409401.7	TSL:1	c.542T>C	p.Ile181Thr	missense	Exon 6 of 7	ENSP00000386594.3	Q8IYB7-4
	DIS3L2	ENST00000390005.9	TSL:1	n.542T>C		non_coding_transcript_exon	Exon 6 of 21	ENSP00000374655.5	Q8IYB7-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.81
DANN	Benign	0.64
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.23
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.56	N
REVEL	Benign	0.045
Sift	Benign	0.41	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.086
MutPred		0.55		Gain of disorder (P = 0.0151)
MVP		0.043
MPC		0.28
ClinPred		0.026	T
GERP RS		-4.3
Varity_R		0.028
gMVP		0.13
Mutation Taster		=98/2	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: rs1060503029; hg19: chr2-232952372;