rs763103187

Variant names:

• chr2-232334636-T-C
• rs763103187
• NM_152383.5:c.2295T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_152383.5(DIS3L2):​c.2295T>C​(p.Ser765Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 149,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.406
• Publications: 3 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.122).
• BP6: Variant 2-232334636-T-C is Benign according to our data. Variant chr2-232334636-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 241973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.406 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	NM_152383.5	MANE Select	c.2295T>C	p.Ser765Ser	synonymous	Exon 19 of 21	NP_689596.4
	DIS3L2	NR_046476.2		n.2368T>C		non_coding_transcript_exon	Exon 19 of 21
	DIS3L2	NR_046477.2		n.2347T>C		non_coding_transcript_exon	Exon 18 of 19

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2295T>C	p.Ser765Ser	synonymous	Exon 19 of 21	ENSP00000315569.7
	DIS3L2	ENST00000390005.9	TSL:1	n.*362T>C		non_coding_transcript_exon	Exon 19 of 21	ENSP00000374655.5
	DIS3L2	ENST00000445090.5	TSL:1	n.*1451T>C		non_coding_transcript_exon	Exon 18 of 19	ENSP00000388999.1

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 393 AN: 149878 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.00161 AC: 352 AN: 218886 AF XY: 0.00142

Gnomad AFR exome AF: 0.0177

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00139

Gnomad FIN exome AF: 0.000523

Gnomad NFE exome AF: 0.000348

Gnomad OTH exome AF: 0.000552

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000656 AC: 937 AN: 1427840 Hom.: 0 Cov.: 33 AF XY: 0.000642 AC XY: 455 AN XY: 709074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0155 AC: 488 AN: 31458

American (AMR) AF: 0.00172 AC: 71 AN: 41348

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25422

East Asian (EAS) AF: 0.00140 AC: 53 AN: 37968

South Asian (SAS) AF: 0.000533 AC: 44 AN: 82536

European-Finnish (FIN) AF: 0.000292 AC: 15 AN: 51394

Middle Eastern (MID) AF: 0.00197 AC: 11 AN: 5576

European-Non Finnish (NFE) AF: 0.000163 AC: 178 AN: 1093256

Other (OTH) AF: 0.00126 AC: 74 AN: 58882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00262 AC: 393 AN: 149990 Hom.: 0 Cov.: 33 AF XY: 0.00248 AC XY: 182 AN XY: 73364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00913 AC: 363 AN: 39754

American (AMR) AF: 0.00105 AC: 16 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3460

East Asian (EAS) AF: 0.000788 AC: 4 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67844

Other (OTH) AF: 0.00145 AC: 3 AN: 2070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00233 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.4
DANN	Benign	0.60
PhyloP100		-0.41
PromoterAI		0.0049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs763103187; hg19: chr2-233199346; COSMIC: COSV99807410; COSMIC: COSV99807410;