rs12495784

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025265.4(TSEN2):c.122G>A(p.Arg41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,613,910 control chromosomes in the GnomAD database, including 1,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.065 ( 698 hom., cov: 32)

Exomes 𝑓: 0.022 ( 1036 hom. )

Consequence

TSEN2
NM_025265.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.262

Publications

14 publications found

Variant links:

Genes affected

TSEN2 (HGNC:28422): (tRNA splicing endonuclease subunit 2) This gene encodes one of the subunits of the tRNA splicing endonuclease. This endonuclease catalyzes the first step in RNA splicing which is the removal of introns. Mutations in this gene have been associated with pontocerebellar hypoplasia type 2. A pseudogene has been identified on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

TSEN2 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2B
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TSEN2 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=0.001170665).

BP6

Variant 3-12489922-G-A is Benign according to our data. Variant chr3-12489922-G-A is described in ClinVar as Benign. ClinVar VariationId is 137752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN2	NM_025265.4 link	c.122G>A	p.Arg41His	missense_variant	Exon 2 of 12	ENST00000284995.11	NP_079541.1	Q8NCE0-1A0A024R2G3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11 link	c.122G>A	p.Arg41His	missense_variant	Exon 2 of 12	1	NM_025265.4	ENSP00000284995.6		Q8NCE0-1

Frequencies

GnomAD3 genomes

AF:

0.0646

AC:

9828

AN:

152054

Hom.:

694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0687

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0374

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0725

GnomAD2 exomes

AF:

0.0354

AC:

8907

AN:

251432

AF XY:

0.0329

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.0338

Gnomad FIN exome

AF:

0.00971

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0318

GnomAD4 exome

AF:

0.0221

AC:

32265

AN:

1461738

Hom.:

1036

Cov.:

AF XY:

0.0221

AC XY:

16058

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.175

AC:

5850

AN:

33462

American (AMR)

AF:

0.0488

AC:

2182

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

26136

East Asian (EAS)

AF:

0.0436

AC:

1730

AN:

39698

South Asian (SAS)

AF:

0.0556

AC:

4793

AN:

86246

European-Finnish (FIN)

AF:

0.0102

AC:

546

AN:

53390

Middle Eastern (MID)

AF:

0.0246

AC:

142

AN:

5768

European-Non Finnish (NFE)

AF:

0.0136

AC:

15085

AN:

1111928

Other (OTH)

AF:

0.0305

AC:

1839

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

1905

3810

5715

7620

9525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.0647

AC:

9843

AN:

152172

Hom.:

698

Cov.:

AF XY:

0.0646

AC XY:

4811

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.169

AC:

7012

AN:

41488

American (AMR)

AF:

0.0687

AC:

1050

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.0377

AC:

195

AN:

5176

South Asian (SAS)

AF:

0.0600

AC:

289

AN:

4820

European-Finnish (FIN)

AF:

0.0107

AC:

113

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0147

AC:

1002

AN:

68016

Other (OTH)

AF:

0.0750

AC:

158

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

421

842

1262

1683

2104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0276

Hom.:

598

Bravo

AF:

0.0727

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.159

AC:

699

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.0381

AC:

4628

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jun 04, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pontoneocerebellar hypoplasia

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.027

T;.;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.45

T;T;.;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;L;L;L;L

PhyloP100

-0.26

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N

REVEL

Benign

0.050

Sift

Benign

0.10

T;T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.033, 0.074

.;.;B;.;B;B

Vest4

0.032, 0.028

MPC

0.035

ClinPred

0.0067

GERP RS

-1.6

PromoterAI

-0.040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.39

Mutation Taster

=100/0

polymorphism (auto)

(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