2-74514864-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016170.5(TLX2):ā€‹c.58G>Cā€‹(p.Gly20Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00021 ( 0 hom., cov: 33)
Exomes š‘“: 0.00042 ( 0 hom. )

Consequence

TLX2
NM_016170.5 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.92
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TLX2NM_016170.5 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/3 ENST00000233638.8 NP_057254.1 O43763

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TLX2ENST00000233638.8 linkuse as main transcriptc.58G>C p.Gly20Arg missense_variant 1/31 NM_016170.5 ENSP00000233638.6 O43763
TLX2ENST00000621092.1 linkuse as main transcriptc.11+630G>C intron_variant 1 ENSP00000482690.1 F1T0F2
TLX2ENST00000497238.1 linkuse as main transcriptn.522-158G>C intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000129
AC:
32
AN:
248146
Hom.:
0
AF XY:
0.000141
AC XY:
19
AN XY:
135050
show subpopulations
Gnomad AFR exome
AF:
0.000257
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000251
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000416
AC:
607
AN:
1460736
Hom.:
0
Cov.:
34
AF XY:
0.000356
AC XY:
259
AN XY:
726738
show subpopulations
Gnomad4 AFR exome
AF:
0.0000600
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000532
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000210
AC:
32
AN:
152330
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000272
Hom.:
0
Bravo
AF:
0.000181
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.000157
AC:
19
EpiCase
AF:
0.000218
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 31, 2023The c.58G>C (p.G20R) alteration is located in exon 1 (coding exon 1) of the TLX2 gene. This alteration results from a G to C substitution at nucleotide position 58, causing the glycine (G) at amino acid position 20 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.88
D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Pathogenic
0.90
D
PROVEAN
Pathogenic
-4.5
D
REVEL
Pathogenic
0.75
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.83
MVP
0.97
MPC
2.4
ClinPred
0.67
D
GERP RS
4.4
Varity_R
0.69
gMVP
0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200296220; hg19: chr2-74741991; API