2-232263229-G-A

Variant names:

• chr2-232263229-G-A
• rs148474013
• NM_152383.5:c.1448G>A
• DIS3L2 p.Arg483Gln

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152383.5(DIS3L2):​c.1448G>A​(p.Arg483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00561 in 1,614,180 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0085 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (113 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.43
• Publications: 10 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058790445).
• BP6: Variant 2-232263229-G-A is Benign according to our data. Variant chr2-232263229-G-A is described in ClinVar as Benign. ClinVar VariationId is 262630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

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.1448G>A	p.Arg483Gln	missense	Exon 13 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1448G>A	p.Arg483Gln	missense	Exon 13 of 14	NP_001244210.1	Q8IYB7-3
	DIS3L2	NR_046476.2		n.1594G>A		non_coding_transcript_exon	Exon 13 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1448G>A	p.Arg483Gln	missense	Exon 13 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000390005.9	TSL:1	n.1448G>A		non_coding_transcript_exon	Exon 13 of 21	ENSP00000374655.5	Q8IYB7-2
	DIS3L2	ENST00000445090.5	TSL:1	n.*674G>A		non_coding_transcript_exon	Exon 12 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1290 AN: 152186 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0139 AC: 3456 AN: 249342 AF XY: 0.0127

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0180

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00531 AC: 7761 AN: 1461876 Hom.: 113 Cov.: 31 AF XY: 0.00549 AC XY: 3996 AN XY: 727236

African (AFR) AF: 0.000777 AC: 26 AN: 33480

American (AMR) AF: 0.0562 AC: 2512 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00134 AC: 35 AN: 26134

East Asian (EAS) AF: 0.0132 AC: 523 AN: 39698

South Asian (SAS) AF: 0.0173 AC: 1489 AN: 86250

European-Finnish (FIN) AF: 0.0126 AC: 672 AN: 53420

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00196 AC: 2174 AN: 1112008

Other (OTH) AF: 0.00525 AC: 317 AN: 60396

GnomAD4 genome AF: 0.00847 AC: 1290 AN: 152304 Hom.: 23 Cov.: 33 AF XY: 0.0108 AC XY: 802 AN XY: 74474

African (AFR) AF: 0.00147 AC: 61 AN: 41568

American (AMR) AF: 0.0484 AC: 741 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5188

South Asian (SAS) AF: 0.0170 AC: 82 AN: 4828

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68022

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00350 Hom.: 21

Bravo AF: 0.00980

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.00234

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Perlman syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Varity_R		0.86
gMVP		0.71
Mutation Taster		=92/8	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs148474013;

hg19: chr2-233127939;