2-74514952-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016170.5(TLX2):​c.146C>T​(p.Ala49Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

TLX2
NM_016170.5 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.177
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1988622).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TLX2NM_016170.5 linkc.146C>T p.Ala49Val missense_variant Exon 1 of 3 ENST00000233638.8 NP_057254.1 O43763

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TLX2ENST00000233638.8 linkc.146C>T p.Ala49Val missense_variant Exon 1 of 3 1 NM_016170.5 ENSP00000233638.6 O43763
TLX2ENST00000621092.1 linkc.12-681C>T intron_variant Intron 2 of 3 1 ENSP00000482690.1 F1T0F2
TLX2ENST00000497238.1 linkn.522-70C>T intron_variant Intron 2 of 3 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 22, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.146C>T (p.A49V) alteration is located in exon 1 (coding exon 1) of the TLX2 gene. This alteration results from a C to T substitution at nucleotide position 146, causing the alanine (A) at amino acid position 49 to be replaced by a valine (V). 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
Benign
0.071
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T
Eigen
Benign
-0.84
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.16
N
LIST_S2
Benign
0.49
T
M_CAP
Pathogenic
0.78
D
MetaRNN
Benign
0.20
T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
0.81
L
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.85
N
REVEL
Benign
0.11
Sift
Benign
0.40
T
Sift4G
Benign
0.40
T
Polyphen
0.0090
B
Vest4
0.22
MutPred
0.29
Gain of sheet (P = 0.0149);
MVP
0.68
MPC
1.1
ClinPred
0.045
T
GERP RS
-0.093
Varity_R
0.077
gMVP
0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74742079; API