2-232343413-A-AGGG

Variant names:

• chr2-232343413-A-AGGG
• rs141560952
• NM_001257281.2:c.1651_1652insGGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001257281.2(DIS3L2):​c.1651_1652insGGG​(p.Glu550_Ala551insGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,556,686 control chromosomes in the GnomAD database, including 15 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: DIS3L2 NM_001257281.2 disruptive_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.32

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]

NRBF2P6 (HGNC:54797): (NRBF2 pseudogene 6)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001257281.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 2-232343413-A-AGGG is Benign according to our data. Variant chr2-232343413-A-AGGG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1298857.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00232 (353/152322) while in subpopulation NFE AF= 0.00422 (287/68024). AF 95% confidence interval is 0.00382. There are 3 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_001257281.2	c.1651_1652insGGG	p.Glu550_Ala551insGly	disruptive_inframe_insertion	Exon 14 of 14		NP_001244210.1
NRBF2P6		n.232343414_232343415insGGG		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000273009.10	c.1651_1652insGGG	p.Glu550_Ala551insGly	disruptive_inframe_insertion	Exon 14 of 14	2		ENSP00000273009.6
NRBF2P6	ENST00000513620.1	n.299_300insGGG		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152204 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00219 AC: 356 AN: 162534 Hom.: 3 AF XY: 0.00219 AC XY: 190 AN XY: 86712

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000356

Gnomad ASJ exome AF: 0.00232

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00133

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.00341

Gnomad OTH exome AF: 0.00218

GnomAD4 exome AF: 0.00250 AC: 3504 AN: 1404364 Hom.: 12 Cov.: 30 AF XY: 0.00246 AC XY: 1708 AN XY: 693196

Gnomad4 AFR exome AF: 0.000284

Gnomad4 AMR exome AF: 0.000442

Gnomad4 ASJ exome AF: 0.00261

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00321

Gnomad4 NFE exome AF: 0.00279

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00232 AC: 353 AN: 152322 Hom.: 3 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74486

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00507 Hom.: 4

Bravo AF: 0.00148

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DIS3L2: PM4:Supporting, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perlman syndrome Benign:2

Oct 09, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 22, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

DIS3L2-related disorder Benign:1

Nov 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141560952; hg19: chr2-233208123;