chr2-232343406-A-AT

Variant names:

• chr2-232343406-A-AT
• NM_001257281.2:c.1644dupT

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001257281.2(DIS3L2):​c.1644dupT​(p.Ala549CysfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,490 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DIS3L2 NM_001257281.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.113
• 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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0922 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257281.2. 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_001257281.2		c.1644dupT	p.Ala549CysfsTer13	frameshift	Exon 14 of 14	NP_001244210.1	Q8IYB7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000273009.10	TSL:2	c.1644dupT	p.Ala549CysfsTer13	frameshift	Exon 14 of 14	ENSP00000273009.6	Q8IYB7-3
	NRBF2P6	ENST00000513620.1	TSL:6	n.292dupT		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404490 Hom.: 0 Cov.: 30 AF XY: 0.00000144 AC XY: 1 AN XY: 693254

African (AFR) AF: 0.00 AC: 0 AN: 31738

American (AMR) AF: 0.00 AC: 0 AN: 36278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 36138

South Asian (SAS) AF: 0.00 AC: 0 AN: 79804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082370

Other (OTH) AF: 0.00 AC: 0 AN: 58342

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11

Splicing

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

Other links and lift over

hg19: chr2-233208116;