rs1378013232

Variant names:

• chr2-74515726-C-G
• rs1378013232
• NM_016170.5:c.494C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-74515726-C-G
• chr2-74515726-C-A
• chr2-74515726-C-T

Variant summary

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

The NM_016170.5(TLX2):​c.494C>G​(p.Ser165Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,280 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TLX2 NM_016170.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.362
• 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, 0.833

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.494C>G	p.Ser165Cys	missense	Exon 2 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.494C>G	p.Ser165Cys	missense	Exon 2 of 3	ENSP00000233638.6	O43763
	TLX2	ENST00000621092.1	TSL:1	c.105C>G	p.Leu35Leu	synonymous	Exon 3 of 4	ENSP00000482690.1	F1T0F2
	TLX2	ENST00000497238.1	TSL:5	n.*65C>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461280 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726944

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.36
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.54		Loss of phosphorylation at S165 (P = 0.0197)
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.66
gMVP		0.91
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1378013232; hg19: chr2-74742853; COSMIC: COSV52045433; COSMIC: COSV52045433;