chr2-232238605-T-C

Variant names:

• chr2-232238605-T-C
• rs1553539258
• NM_152383.5:c.1277T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152383.5(DIS3L2):​c.1277T>C​(p.Val426Ala) 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. 14/22 in silico tools predict 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. V426G) 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: 5.71
• 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.255223).

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.1277T>C	p.Val426Ala	missense	Exon 11 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1277T>C	p.Val426Ala	missense	Exon 11 of 14	NP_001244210.1	Q8IYB7-3
	DIS3L2	NR_046476.2		n.1423T>C		non_coding_transcript_exon	Exon 11 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1277T>C	p.Val426Ala	missense	Exon 11 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000390005.9	TSL:1	n.1277T>C		non_coding_transcript_exon	Exon 11 of 21	ENSP00000374655.5	Q8IYB7-2
	DIS3L2	ENST00000445090.5	TSL:1	n.*503T>C		non_coding_transcript_exon	Exon 10 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.075	N
PhyloP100		5.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.066
Sift	Benign	0.41	T
Sift4G	Benign	0.72	T
Polyphen		0.017	B
Vest4		0.32
MutPred		0.66		Loss of stability (P = 0.0133)
MVP		0.043
MPC		0.38
ClinPred		0.74	D
GERP RS		4.5
Varity_R		0.11
gMVP		0.48
Mutation Taster		=75/25	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: rs1553539258; hg19: chr2-233103315;