2-232130729-T-C

Variant names:

• chr2-232130729-T-C
• rs184764939
• ENST00000409401.7:c.712T>C

Variant summary

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

The ENST00000409401.7(DIS3L2):​c.712T>C​(p.Tyr238His) 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. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y238D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 ENST00000409401.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.560
• Publications: 5 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: 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=0.05905828).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409401.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.702+10T>C		intron	N/A	NP_689596.4
	DIS3L2	NM_001257282.2		c.712T>C	p.Tyr238His	missense	Exon 7 of 7	NP_001244211.1
	DIS3L2	NR_046477.2		n.858T>C		non_coding_transcript_exon	Exon 7 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000409401.7	TSL:1	c.712T>C	p.Tyr238His	missense	Exon 7 of 7	ENSP00000386594.3
	DIS3L2	ENST00000445090.5	TSL:1	n.712T>C		non_coding_transcript_exon	Exon 7 of 19	ENSP00000388999.1
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.702+10T>C		intron	N/A	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	10
DANN	Benign	0.97
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.028	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.56
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.43		Gain of disorder (P = 0.0128)
MVP		0.043
ClinPred		0.077	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs184764939; hg19: chr2-232995439;