19-3000721-G-A

Variant names:

• chr19-3000721-G-A
• rs759754198
• NM_003260.5:c.2050C>T

Variant summary

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

The NM_003260.5(TLE2):​c.2050C>T​(p.Arg684Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000175 in 1,430,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TLE2 NM_003260.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

TLE2 (HGNC:11838): (TLE family member 2, transcriptional corepressor) Enables transcription corepressor activity. Involved in negative regulation of canonical Wnt signaling pathway and negative regulation of transcription, DNA-templated. Located in focal adhesion and nuclear body. [provided by Alliance of Genome Resources, Apr 2022]

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
TLE2	NM_003260.5	c.2050C>T	p.Arg684Trp	missense_variant, splice_region_variant	Exon 19 of 20	ENST00000262953.11	NP_003251.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLE2	ENST00000262953.11	c.2050C>T	p.Arg684Trp	missense_variant, splice_region_variant	Exon 19 of 20	1	NM_003260.5	ENSP00000262953.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000507 AC: 1 AN: 197316 Hom.: 0 AF XY: 0.00000944 AC XY: 1 AN XY: 105918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000116

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000175 AC: 25 AN: 1430960 Hom.: 0 Cov.: 31 AF XY: 0.0000169 AC XY: 12 AN XY: 708748

Gnomad4 AFR exome AF: 0.0000916

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: 0.0000201

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2050C>T (p.R684W) alteration is located in exon 19 (coding exon 19) of the TLE2 gene. This alteration results from a C to T substitution at nucleotide position 2050, causing the arginine (R) at amino acid position 684 to be replaced by a tryptophan (W). 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	0.26
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.6	D;D;D;.
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.63
MutPred		0.61		Loss of MoRF binding (P = 0.0588);.;.;.;
MVP		0.74
MPC		1.5
ClinPred		0.96	D
GERP RS		1.5
Varity_R		0.35
gMVP		0.65

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

LitVar

Other links and lift over

dbSNP: rs759754198; hg19: chr19-3000719;