rs1057445

Variant names:

• chr2-232130723-A-G
• rs1057445
• ENST00000409401.7:c.706A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001257282.2(DIS3L2):​c.706A>G​(p.Ile236Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: DIS3L2 NM_001257282.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.770
• 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]

DIS3L2 Gene-Disease associations (from GenCC):

• Perlman syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-232130723-A-G is Benign according to our data. Variant chr2-232130723-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 241984.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000368 (56/152314) while in subpopulation AFR AF = 0.00135 (56/41560). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257282.2. 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_152383.5	MANE Select	c.702+4A>G		splice_region intron	N/A	NP_689596.4
	DIS3L2	NM_001257282.2		c.706A>G	p.Ile236Val	missense	Exon 7 of 7	NP_001244211.1	Q8IYB7-4
	DIS3L2	NM_001257281.2		c.702+4A>G		splice_region intron	N/A	NP_001244210.1	Q8IYB7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3L2	ENST00000409401.7	TSL:1	c.706A>G	p.Ile236Val	missense	Exon 7 of 7	ENSP00000386594.3	Q8IYB7-4
	DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.702+4A>G		splice_region intron	N/A	ENSP00000315569.7	Q8IYB7-1
	DIS3L2	ENST00000445090.5	TSL:1	n.706A>G		non_coding_transcript_exon	Exon 7 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000846 AC: 21 AN: 248342 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00129

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: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1461354 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 726956

African (AFR) AF: 0.00146 AC: 49 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111762

Other (OTH) AF: 0.0000331 AC: 2 AN: 60378

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74492

African (AFR) AF: 0.00135 AC: 56 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000470 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000993 AC: 12

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.52
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.082	N
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.77
PROVEAN	Benign	0.42	N
REVEL	Benign	0.031
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.13
ClinPred		0.0078	T
GERP RS		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.24		Position offset: -4

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

Other links and lift over

dbSNP: rs1057445; hg19: chr2-232995433;