chr2-74514864-G-A

Variant names:

• chr2-74514864-G-A
• rs200296220
• NM_016170.5:c.58G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016170.5(TLX2):​c.58G>A​(p.Gly20Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G20R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLX2 NM_016170.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.92
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016170.5. 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.58G>A	p.Gly20Ser	missense	Exon 1 of 3	NP_057254.1	O43763

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX2	ENST00000233638.8	TSL:1 MANE Select	c.58G>A	p.Gly20Ser	missense	Exon 1 of 3	ENSP00000233638.6	O43763
	TLX2	ENST00000621092.1	TSL:1	c.11+630G>A		intron	N/A	ENSP00000482690.1	F1T0F2
	TLX2	ENST00000497238.1	TSL:5	n.522-158G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460738 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726740

African (AFR) AF: 0.00 AC: 0 AN: 33320

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111656

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.60
Sift	Benign	0.18	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.28		Gain of glycosylation at G20 (P = 0.0161)
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.048	Neutral
Varity_R		0.25
gMVP		0.78
Mutation Taster		=49/51	disease causing

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

Other links and lift over

dbSNP: rs200296220; hg19: chr2-74741991;