NM_152383.5:c.-78C>T

Variant names:

• chr2-232014850-C-T
• rs114491317
• NM_152383.5:c.-78C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152383.5(DIS3L2):​c.-78C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,485,644 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: DIS3L2 NM_152383.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.34
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-232014850-C-T is Benign according to our data. Variant chr2-232014850-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 895500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0028 (427/152342) while in subpopulation NFE AF = 0.00466 (317/68034). AF 95% confidence interval is 0.00424. There are 1 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	NP_689596.4
	DIS3L2	NM_152383.5	MANE Select	c.-78C>T		5_prime_UTR	Exon 2 of 21	NP_689596.4
	DIS3L2	NM_001257281.2		c.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 14	NP_001244210.1	Q8IYB7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000409401.7	TSL:1	c.-78C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000386594.3	Q8IYB7-4
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.-78C>T		5_prime_UTR	Exon 2 of 21	ENSP00000315569.7	Q8IYB7-1

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 427 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00284 AC: 3793 AN: 1333302 Hom.: 5 Cov.: 18 AF XY: 0.00286 AC XY: 1912 AN XY: 668438

African (AFR) AF: 0.000501 AC: 15 AN: 29918

American (AMR) AF: 0.000315 AC: 13 AN: 41246

Ashkenazi Jewish (ASJ) AF: 0.00919 AC: 226 AN: 24600

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38770

South Asian (SAS) AF: 0.00221 AC: 178 AN: 80396

European-Finnish (FIN) AF: 0.00207 AC: 108 AN: 52080

Middle Eastern (MID) AF: 0.00244 AC: 12 AN: 4920

European-Non Finnish (NFE) AF: 0.00308 AC: 3098 AN: 1005450

Other (OTH) AF: 0.00254 AC: 142 AN: 55922

GnomAD4 genome AF: 0.00280 AC: 427 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00263 AC XY: 196 AN XY: 74496

African (AFR) AF: 0.000553 AC: 23 AN: 41582

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00237

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.60
PhyloP100		1.3
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs114491317; hg19: chr2-232879560;