2-74516031-C-T

Variant names:

• chr2-74516031-C-T
• NM_016170.5:c.697C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016170.5(TLX2):​c.697C>T​(p.His233Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLX2 NM_016170.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLX2	NM_016170.5	c.697C>T	p.His233Tyr	missense_variant	Exon 3 of 3	ENST00000233638.8	NP_057254.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLX2	ENST00000233638.8	c.697C>T	p.His233Tyr	missense_variant	Exon 3 of 3	1	NM_016170.5	ENSP00000233638.6
TLX2	ENST00000621092.1	c.308C>T	p.Ala103Val	missense_variant	Exon 4 of 4	1		ENSP00000482690.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404818 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 696518

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.697C>T (p.H233Y) alteration is located in exon 3 (coding exon 3) of the TLX2 gene. This alteration results from a C to T substitution at nucleotide position 697, causing the histidine (H) at amino acid position 233 to be replaced by a tyrosine (Y). 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	0.20
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.62	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.68
ClinPred		0.92	D
GERP RS		3.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-74743158;