chr2-232329949-G-C

Position:

• chr2-232329949-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152383.5(DIS3L2):​c.1876G>C​(p.Asp626His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.739

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058943957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1876G>C	p.Asp626His	missense_variant	15/21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-13396G>C		intron_variant			NP_001244210.1
DIS3L2	NR_046476.2	n.1949G>C		non_coding_transcript_exon_variant	15/21
DIS3L2	NR_046477.2	n.1928G>C		non_coding_transcript_exon_variant	14/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1876G>C	p.Asp626His	missense_variant	15/21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248194 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460704 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.061	T;T;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T;.;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.12	N;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.031
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.32
MutPred		0.44		Gain of catalytic residue at D626 (P = 0.0094);Gain of catalytic residue at D626 (P = 0.0094);.;
MVP		0.10
MPC		0.29
ClinPred		0.045	T
GERP RS		1.3
Varity_R		0.13
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs374482102; hg19: chr2-233194659;