2-74516012-C-G

Variant names:

• chr2-74516012-C-G
• rs371068999
• ENST00000621092.1:c.289C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000621092.1(TLX2):​c.289C>G​(p.Arg97Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000219 in 1,370,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign 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. R97C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TLX2 ENST00000621092.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08751631).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000621092.1. 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.678C>G	p.Arg226Arg	synonymous	Exon 3 of 3	NP_057254.1	O43763

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLX2	ENST00000621092.1	TSL:1	c.289C>G	p.Arg97Gly	missense	Exon 4 of 4	ENSP00000482690.1	F1T0F2
	TLX2	ENST00000233638.8	TSL:1 MANE Select	c.678C>G	p.Arg226Arg	synonymous	Exon 3 of 3	ENSP00000233638.6	O43763

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1370232 Hom.: 0 Cov.: 31 AF XY: 0.00000295 AC XY: 2 AN XY: 677076

African (AFR) AF: 0.00 AC: 0 AN: 28338

American (AMR) AF: 0.00 AC: 0 AN: 32614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23122

East Asian (EAS) AF: 0.00 AC: 0 AN: 33680

South Asian (SAS) AF: 0.00 AC: 0 AN: 75878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4788

European-Non Finnish (NFE) AF: 0.00000279 AC: 3 AN: 1075310

Other (OTH) AF: 0.00 AC: 0 AN: 56876

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.7
DANN	Benign	0.84
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.088	T
PhyloP100		-0.47
PrimateAI	Benign	0.44	T
Sift4G	Benign	0.54	T
Polyphen		0.044	B
Vest4		0.13
MVP		0.57
GERP RS		0.61
Mutation Taster		=100/0	polymorphism

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: rs371068999; hg19: chr2-74743139;