2-74514952-C-T

Variant names:

• chr2-74514952-C-T
• NM_016170.5:c.146C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.177

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]

ACMG classification

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
TLX2	NM_016170.5	c.146C>T	p.Ala49Val	missense_variant	Exon 1 of 3	ENST00000233638.8	NP_057254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX2	ENST00000233638.8	c.146C>T	p.Ala49Val	missense_variant	Exon 1 of 3	1	NM_016170.5	ENSP00000233638.6
TLX2	ENST00000621092.1	c.12-681C>T		intron_variant	Intron 2 of 3	1		ENSP00000482690.1
TLX2	ENST00000497238.1	n.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

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;