rs187677159

Variant names:

• chr2-232329912-C-T
• rs187677159
• NM_152383.5:c.1839C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-232329912-C-T
• chr2-232329912-C-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_152383.5(DIS3L2):​c.1839C>T​(p.Pro613Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,068 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: DIS3L2 NM_152383.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.337
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.1).
• BP6: Variant 2-232329912-C-T is Benign according to our data. Variant chr2-232329912-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 531986.
• BP7: Synonymous conserved (PhyloP=-0.337 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000397 (58/1460764) while in subpopulation EAS AF = 0.00146 (58/39656). AF 95% confidence interval is 0.00116. There are 1 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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.1839C>T	p.Pro613Pro	synonymous	Exon 15 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1582-13433C>T		intron	N/A	NP_001244210.1	Q8IYB7-3
	DIS3L2	NR_046476.2		n.1912C>T		non_coding_transcript_exon	Exon 15 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1839C>T	p.Pro613Pro	synonymous	Exon 15 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000390005.9	TSL:1	n.1766C>T		non_coding_transcript_exon	Exon 15 of 21	ENSP00000374655.5	Q8IYB7-2
	DIS3L2	ENST00000445090.5	TSL:1	n.*995C>T		non_coding_transcript_exon	Exon 14 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152186 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000645 AC: 16 AN: 248174 AF XY: 0.0000519

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000893

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1460764 Hom.: 1 Cov.: 35 AF XY: 0.0000344 AC XY: 25 AN XY: 726710

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111778

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152304 Hom.: 1 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74464

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Perlman syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_noAF	Benign	-0.29
CADD	Benign	5.1
DANN	Benign	0.94
PhyloP100		-0.34
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs187677159; hg19: chr2-233194622;