2-232014928-A-T

Variant names:

• chr2-232014928-A-T
• rs754758868
• NM_152383.5:c.1A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_152383.5(DIS3L2):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 initiator_codon
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.19
• Publications: 1 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)

ENSG00000227033 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 232014949. Lost 0.008 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>T	p.Met1?	initiator_codon	Exon 2 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 14	NP_001244210.1	Q8IYB7-3
	DIS3L2	NM_001257282.2		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 7	NP_001244211.1	Q8IYB7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000409401.7	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 7	ENSP00000386594.3	Q8IYB7-4
	DIS3L2	ENST00000390005.9	TSL:1	n.1A>T		non_coding_transcript_exon	Exon 2 of 21	ENSP00000374655.5	Q8IYB7-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249262 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	DIS3L2-related disorder (1)
-	1	-	Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.033
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.98	T
PhyloP100		3.2
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.33	B
Vest4		0.81
MutPred		1.0		Loss of MoRF binding (P = 0.0848)
MVP		0.20
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.74
gMVP		0.32
Mutation Taster		=16/184	disease causing

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: rs754758868; hg19: chr2-232879638;