6-166929716-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003730.6(RNASET2):c.643G>A(p.Glu215Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,614,092 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 26 hom. )

Consequence

RNASET2
NM_003730.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.589

Publications

12 publications found

Variant links:

Genes affected

RNASET2 (HGNC:21686): (ribonuclease T2) This ribonuclease gene is a novel member of the Rh/T2/S-glycoprotein class of extracellular ribonucleases. It is a single copy gene that maps to 6q27, a region associated with human malignancies and chromosomal rearrangement. [provided by RefSeq, Jul 2008]

RNASET2 Gene-Disease associations (from GenCC):

cystic leukoencephalopathy without megalencephaly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, Orphanet

RNASET2 links:

ENSG00000249141 (HGNC:):

ENSG00000249141 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005907774).

BP6

Variant 6-166929716-C-T is Benign according to our data. Variant chr6-166929716-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 356030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00437 (666/152238) while in subpopulation AMR AF = 0.0072 (110/15284). AF 95% confidence interval is 0.00611. There are 1 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASET2	NM_003730.6 link	c.643G>A	p.Glu215Lys	missense_variant	Exon 9 of 9	ENST00000508775.6	NP_003721.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASET2	ENST00000508775.6 link	c.643G>A	p.Glu215Lys	missense_variant	Exon 9 of 9	1	NM_003730.6	ENSP00000426455.2
ENSG00000249141	ENST00000507747.1 link	c.432+4375G>A		intron_variant	Intron 7 of 7	5		ENSP00000426906.1

Frequencies

GnomAD3 genomes

AF:

0.00438

AC:

666

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00721

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00598

Gnomad OTH

AF:

0.00719

GnomAD2 exomes

AF:

0.00437

AC:

1098

AN:

251406

AF XY:

0.00411

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00622

Gnomad ASJ exome

AF:

0.0152

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00291

Gnomad NFE exome

AF:

0.00528

Gnomad OTH exome

AF:

0.00815

GnomAD4 exome

AF:

0.00539

AC:

7881

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

3774

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33478

American (AMR)

AF:

0.00662

AC:

296

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

359

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00264

AC:

141

AN:

53392

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00603

AC:

6709

AN:

1112004

Other (OTH)

AF:

0.00522

AC:

315

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

466

933

1399

1866

2332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00437

AC:

666

AN:

152238

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41556

American (AMR)

AF:

0.00720

AC:

110

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0124

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00292

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00598

AC:

407

AN:

68016

Other (OTH)

AF:

0.00712

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00524

Hom.:

Bravo

AF:

0.00458

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00400

AC:

485

EpiCase

AF:

0.00616

EpiControl

AF:

0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RNASET2: BP4, BS2 -

Cystic leukoencephalopathy without megalencephaly

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

RNASET2-related disorder

Benign:1

Apr 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.010

.;T;T;T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

T;.;T;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.9

.;L;.;L;.

PhyloP100

0.59

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

N;N;.;N;N

REVEL

Benign

0.23

Sift

Benign

0.19

T;T;.;T;T

Sift4G

Uncertain

0.027

D;T;D;T;.

Polyphen

0.57

.;P;.;P;.

Vest4

0.17

MVP

0.78

MPC

0.41

ClinPred

0.024

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.098

gMVP

0.46

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over