2-232336618-A-G

Variant names:

• chr2-232336618-A-G
• rs3811578
• NM_152383.5:c.2646A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The ENST00000325385.12(DIS3L2):​c.2646A>G​(p.Ser882Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,603,266 control chromosomes in the GnomAD database, including 13,081 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S882S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1713 hom., cov: 32)
  • Exomes 𝑓: 0.10 (11368 hom.)
• Consequence: DIS3L2 ENST00000325385.12 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.256
• Publications: 15 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.027).
• BP6: Variant 2-232336618-A-G is Benign according to our data. Variant chr2-232336618-A-G is described in ClinVar as Benign. ClinVar VariationId is 262631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.256 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000325385.12. 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.2646A>G	p.Ser882Ser	synonymous	Exon 21 of 21	NP_689596.4
	DIS3L2	NR_046476.2		n.2719A>G		non_coding_transcript_exon	Exon 21 of 21
	DIS3L2	NR_046477.2		n.3292A>G		non_coding_transcript_exon	Exon 19 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2646A>G	p.Ser882Ser	synonymous	Exon 21 of 21	ENSP00000315569.7
	DIS3L2	ENST00000390005.9	TSL:1	n.*713A>G		non_coding_transcript_exon	Exon 21 of 21	ENSP00000374655.5
	DIS3L2	ENST00000390005.9	TSL:1	n.*713A>G		3_prime_UTR	Exon 21 of 21	ENSP00000374655.5

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19115 AN: 151878 Hom.: 1700 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.0801

Gnomad FIN AF: 0.0801

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.144

GnomAD2 exomes AF: 0.143 AC: 32887 AN: 230524 AF XY: 0.132

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0835

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0873

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.101 AC: 146236 AN: 1451268 Hom.: 11368 Cov.: 32 AF XY: 0.0995 AC XY: 71861 AN XY: 721996

African (AFR) AF: 0.151 AC: 5032 AN: 33406

American (AMR) AF: 0.248 AC: 10947 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 2270 AN: 26064

East Asian (EAS) AF: 0.481 AC: 19004 AN: 39510

South Asian (SAS) AF: 0.0778 AC: 6656 AN: 85514

European-Finnish (FIN) AF: 0.0896 AC: 4150 AN: 46310

Middle Eastern (MID) AF: 0.113 AC: 639 AN: 5660

European-Non Finnish (NFE) AF: 0.0815 AC: 90536 AN: 1110558

Other (OTH) AF: 0.116 AC: 7002 AN: 60118

GnomAD4 genome AF: 0.126 AC: 19152 AN: 151998 Hom.: 1713 Cov.: 32 AF XY: 0.127 AC XY: 9437 AN XY: 74294

African (AFR) AF: 0.153 AC: 6329 AN: 41454

American (AMR) AF: 0.183 AC: 2792 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 292 AN: 3468

East Asian (EAS) AF: 0.458 AC: 2345 AN: 5124

South Asian (SAS) AF: 0.0789 AC: 380 AN: 4814

European-Finnish (FIN) AF: 0.0801 AC: 848 AN: 10592

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0849 AC: 5769 AN: 67954

Other (OTH) AF: 0.144 AC: 304 AN: 2112

Alfa AF: 0.0955 Hom.: 1210

Bravo AF: 0.140

Asia WGS AF: 0.222 AC: 771 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Perlman syndrome (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.0
DANN	Benign	0.52
PhyloP100		-0.26
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: rs3811578; hg19: chr2-233201328; COSMIC: COSV56053495; COSMIC: COSV56053495;