Genetic Variant NM_025265.4:c.1389C>G (chr3-12532712-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_025265.4(TSEN2):c.1389C>G(p.Asp463Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D463D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSEN2
NM_025265.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.90

Publications

2 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 links:

MKRN2OS (HGNC:40375): (MKRN2 opposite strand)

MKRN2OS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055998623).

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	UniProt
TSEN2	NM_025265.4	MANE Select	c.1389C>G	p.Asp463Glu	missense	Exon 12 of 12	NP_079541.1	Q8NCE0-1
TSEN2	NM_001145392.2		c.1389C>G	p.Asp463Glu	missense	Exon 12 of 12	NP_001138864.1	Q8NCE0-1
TSEN2	NM_001321277.2		c.1389C>G	p.Asp463Glu	missense	Exon 12 of 12	NP_001308206.1	Q8NCE0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.1389C>G	p.Asp463Glu	missense	Exon 12 of 12	ENSP00000284995.6	Q8NCE0-1
TSEN2	ENST00000402228.7	TSL:1	c.1389C>G	p.Asp463Glu	missense	Exon 12 of 12	ENSP00000385976.3	Q8NCE0-1
TSEN2	ENST00000454502.6	TSL:1	c.1212C>G	p.Asp404Glu	missense	Exon 13 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251440

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000163

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111932

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.0040

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.024

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.66

M_CAP

Benign

0.028

MetaRNN

Benign

0.056

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.74

PhyloP100

-2.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

REVEL

Benign

0.091

Sift

Benign

0.34

Sift4G

Benign

0.49

Polyphen

0.75

Vest4

0.081

MutPred

0.15

Gain of glycosylation at S460 (P = 0.0012)

MVP

0.32

MPC

0.039

ClinPred

0.58

GERP RS

-9.1

Varity_R

0.069

gMVP

0.11

Mutation Taster

=82/18

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over