rs2697798

chr2-232334670-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152383.5(DIS3L2):c.2329A>G(p.Ile777Val) variant causes a missense change. The variant allele was found at a frequency of 0.000131 in 152,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I777M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.87

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022104353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.2329A>G	p.Ile777Val	missense_variant	19/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1582-8675A>G		intron_variant
DIS3L2	NR_046476.2	n.2402A>G		non_coding_transcript_exon_variant	19/21
DIS3L2	NR_046477.2	n.2381A>G		non_coding_transcript_exon_variant	18/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2329A>G	p.Ile777Val	missense_variant	19/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152086 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000185 AC: 262 AN: 1418476 Hom.: 0 Cov.: 33 AF XY: 0.000214 AC XY: 151 AN XY: 705340

Gnomad4 AFR exome AF: 0.000248

Gnomad4 AMR exome AF: 0.000544

Gnomad4 ASJ exome AF: 0.000275

Gnomad4 EAS exome AF: 0.000338

Gnomad4 SAS exome AF: 0.000387

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000306

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152204 Hom.: 1 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74408

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000240 Hom.: 0

ExAC AF: 0.00108 AC: 131

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Perlman syndrome Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 18, 2022	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	16
Dann	Benign	0.61
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.29	T;.
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.5	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.54	N;N
REVEL	Benign	0.071
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.17
MVP		0.043
MPC		0.18
ClinPred		0.14	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs2697798; hg19: chr2-233199380; COSMIC: COSV56053242; COSMIC: COSV56053242;