chr2-232210371-C-T

Variant names:

• chr2-232210371-C-T
• rs17272089
• NM_152383.5:c.1170C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_152383.5(DIS3L2):​c.1170C>T​(p.Leu390Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.025 in 1,613,548 control chromosomes in the GnomAD database, including 638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 32)
  • Exomes 𝑓: 0.026 (599 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.681
• Publications: 7 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-232210371-C-T is Benign according to our data. Variant chr2-232210371-C-T is described in ClinVar as Benign. ClinVar VariationId is 334936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.681 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0176 (2688/152304) while in subpopulation SAS AF = 0.0447 (215/4810). AF 95% confidence interval is 0.0398. There are 39 homozygotes in GnomAd4. There are 1252 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

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.1170C>T	p.Leu390Leu	synonymous	Exon 10 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1170C>T	p.Leu390Leu	synonymous	Exon 10 of 14	NP_001244210.1	Q8IYB7-3
	DIS3L2	NR_046476.2		n.1316C>T		non_coding_transcript_exon	Exon 10 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1170C>T	p.Leu390Leu	synonymous	Exon 10 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000390005.9	TSL:1	n.1170C>T		non_coding_transcript_exon	Exon 10 of 21	ENSP00000374655.5	Q8IYB7-2
	DIS3L2	ENST00000445090.5	TSL:1	n.*396C>T		non_coding_transcript_exon	Exon 9 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2687 AN: 152186 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00475

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0440

Gnomad FIN AF: 0.00886

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0225

GnomAD2 exomes AF: 0.0215 AC: 5373 AN: 249530 AF XY: 0.0234

Gnomad AFR exome AF: 0.00452

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.0290

Gnomad EAS exome AF: 0.000222

Gnomad FIN exome AF: 0.00988

Gnomad NFE exome AF: 0.0257

Gnomad OTH exome AF: 0.0243

GnomAD4 exome AF: 0.0258 AC: 37725 AN: 1461244 Hom.: 599 Cov.: 31 AF XY: 0.0264 AC XY: 19169 AN XY: 726942

African (AFR) AF: 0.00442 AC: 148 AN: 33470

American (AMR) AF: 0.0143 AC: 640 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 743 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39682

South Asian (SAS) AF: 0.0401 AC: 3459 AN: 86246

European-Finnish (FIN) AF: 0.00914 AC: 488 AN: 53376

Middle Eastern (MID) AF: 0.0372 AC: 214 AN: 5760

European-Non Finnish (NFE) AF: 0.0274 AC: 30508 AN: 1111520

Other (OTH) AF: 0.0252 AC: 1521 AN: 60362

GnomAD4 genome AF: 0.0176 AC: 2688 AN: 152304 Hom.: 39 Cov.: 32 AF XY: 0.0168 AC XY: 1252 AN XY: 74464

African (AFR) AF: 0.00474 AC: 197 AN: 41576

American (AMR) AF: 0.0131 AC: 200 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0447 AC: 215 AN: 4810

European-Finnish (FIN) AF: 0.00886 AC: 94 AN: 10612

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0264 AC: 1794 AN: 68032

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0232 Hom.: 24

Bravo AF: 0.0169

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0286

EpiControl AF: 0.0270

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.1
DANN	Benign	0.80
PhyloP100		-0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs17272089; hg19: chr2-233075081; COSMIC: COSV56047717;