rs33955793

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.377G>A(p.Arg126His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0675 in 1,614,116 control chromosomes in the GnomAD database, including 5,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R126C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.072 ( 524 hom., cov: 32)

Exomes 𝑓: 0.067 ( 4890 hom. )

Consequence

TSEN2
NM_025265.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.112

Publications

19 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=0.0057552755).

BP6

Variant 3-12503330-G-A is Benign according to our data. Variant chr3-12503330-G-A is described in ClinVar as Benign. ClinVar VariationId is 96175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025265.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSEN2	NM_025265.4	MANE Select	c.377G>A	p.Arg126His	missense	Exon 5 of 12	NP_079541.1
TSEN2	NM_001321278.2		c.377G>A	p.Arg126His	missense	Exon 5 of 12	NP_001308207.1
TSEN2	NM_001145392.2		c.377G>A	p.Arg126His	missense	Exon 5 of 12	NP_001138864.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.377G>A	p.Arg126His	missense	Exon 5 of 12	ENSP00000284995.6
TSEN2	ENST00000402228.7	TSL:1	c.377G>A	p.Arg126His	missense	Exon 5 of 12	ENSP00000385976.3
TSEN2	ENST00000454502.6	TSL:1	c.377G>A	p.Arg126His	missense	Exon 5 of 13	ENSP00000392029.2

Frequencies

GnomAD3 genomes

AF:

0.0720

AC:

10957

AN:

152128

Hom.:

522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0354

Gnomad FIN

AF:

0.0768

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0640

Gnomad OTH

AF:

0.0621

GnomAD2 exomes

AF:

0.0873

AC:

21940

AN:

251324

AF XY:

0.0773

show subpopulations

Gnomad AFR exome

AF:

0.0640

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.0366

Gnomad EAS exome

AF:

0.0133

Gnomad FIN exome

AF:

0.0771

Gnomad NFE exome

AF:

0.0606

Gnomad OTH exome

AF:

0.0794

GnomAD4 exome

AF:

0.0670

AC:

97900

AN:

1461870

Hom.:

4890

Cov.:

AF XY:

0.0644

AC XY:

46830

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0641

AC:

2145

AN:

33480

American (AMR)

AF:

0.280

AC:

12511

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0374

AC:

978

AN:

26136

East Asian (EAS)

AF:

0.0128

AC:

510

AN:

39700

South Asian (SAS)

AF:

0.0334

AC:

2879

AN:

86256

European-Finnish (FIN)

AF:

0.0772

AC:

4126

AN:

53420

Middle Eastern (MID)

AF:

0.0264

AC:

152

AN:

5766

European-Non Finnish (NFE)

AF:

0.0638

AC:

70920

AN:

1111996

Other (OTH)

AF:

0.0609

AC:

3679

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

5400

10800

16201

21601

27001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2708

5416

8124

10832

13540

<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:

0.0721

AC:

10973

AN:

152246

Hom.:

524

Cov.:

AF XY:

0.0728

AC XY:

5421

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0665

AC:

2762

AN:

41528

American (AMR)

AF:

0.160

AC:

2445

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0351

AC:

122

AN:

3472

East Asian (EAS)

AF:

0.0160

AC:

AN:

5184

South Asian (SAS)

AF:

0.0354

AC:

171

AN:

4828

European-Finnish (FIN)

AF:

0.0768

AC:

815

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0640

AC:

4351

AN:

68014

Other (OTH)

AF:

0.0620

AC:

131

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

509

1018

1527

2036

2545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0598

Hom.:

397

Bravo

AF:

0.0809

ESP6500AA

AF:

0.0608

AC:

268

ESP6500EA

AF:

0.0662

AC:

569

ExAC

AF:

0.0778

AC:

9444

EpiCase

AF:

0.0544

EpiControl

AF:

0.0546

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.3

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.023

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.094

MetaRNN

Benign

0.0058

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

PhyloP100

-0.11

PrimateAI

Benign

0.22

PROVEAN

Benign

0.66

REVEL

Benign

0.10

Sift

Benign

0.37

Sift4G

Benign

0.26

Polyphen

0.0010

Vest4

0.14

MPC

0.034

ClinPred

0.0065

GERP RS

-9.2

Varity_R

0.012

gMVP

0.17

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over