Genetic Variant TLX2:p.Arg97Cys (chr2-74516012-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The ENST00000621092.1(TLX2):c.289C>T(p.Arg97Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,522,418 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00066 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 7 hom. )

Consequence

TLX2
ENST00000621092.1 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.474

Publications

0 publications found

Variant links:

Genes affected

TLX2 (HGNC:5057): (T cell leukemia homeobox 2) This gene is a member of an orphan homeobox-containing transcription factor family. Studies of the mouse ortholog have shown that the encoded protein is crucial for the development of the enteric nervous system; in humans, loss-of-function may play a role in tumorigenesis of gastrointestinal stromal tumors. [provided by RefSeq, May 2010]

TLX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024291873).

BP6

Variant 2-74516012-C-T is Benign according to our data. Variant chr2-74516012-C-T is described in ClinVar as Benign. ClinVar VariationId is 716444.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000621092.1. 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
	TLX2	NM_016170.5	MANE Select	c.678C>T	p.Arg226Arg	synonymous	Exon 3 of 3	NP_057254.1	O43763

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX2	ENST00000621092.1	TSL:1	c.289C>T	p.Arg97Cys	missense	Exon 4 of 4	ENSP00000482690.1	F1T0F2
	TLX2	ENST00000233638.8	TSL:1 MANE Select	c.678C>T	p.Arg226Arg	synonymous	Exon 3 of 3	ENSP00000233638.6	O43763

Frequencies

GnomAD3 genomes

AF:

0.000651

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00175

AC:

213

AN:

121884

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.000565

Gnomad AMR exome

AF:

0.0000477

Gnomad ASJ exome

AF:

0.000331

Gnomad EAS exome

AF:

0.0243

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000878

GnomAD4 exome

AF:

0.000289

AC:

396

AN:

1370232

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

164

AN XY:

677076

show subpopulations

African (AFR)

AF:

0.000247

AC:

AN:

28338

American (AMR)

AF:

0.0000307

AC:

AN:

32614

Ashkenazi Jewish (ASJ)

AF:

0.0000865

AC:

AN:

23122

East Asian (EAS)

AF:

0.00775

AC:

261

AN:

33680

South Asian (SAS)

AF:

0.000105

AC:

AN:

75878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4788

European-Non Finnish (NFE)

AF:

0.00000465

AC:

AN:

1075310

Other (OTH)

AF:

0.00197

AC:

112

AN:

56876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

120

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000664

AC:

101

AN:

152186

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41534

American (AMR)

AF:

0.000131

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0163

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67982

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

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:

0.0000461

Hom.:

Bravo

AF:

0.000608

ExAC

AF:

0.00129

AC:

137

Asia WGS

AF:

0.00782

AC:

AN:

3468

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

9.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.35

FATHMM_MKL

Benign

0.52

MetaRNN

Benign

0.0024

PhyloP100

-0.47

PrimateAI

Uncertain

0.49

Sift4G

Benign

0.13

Polyphen

0.12

Vest4

0.16

MVP

0.56

GERP RS

0.61

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

Computational scores

Splicing

Publications

Other links and lift over