19-2997941-G-A

Variant names:

• chr19-2997941-G-A
• rs373620175
• ENST00000591529.5:c.2104C>T

Variant summary

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

The NM_001144761.2(TLE2):​c.2104C>T​(p.Leu702Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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. L702V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TLE2 NM_001144761.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 0 publications found

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

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=0.08762431).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001144761.2. 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
	TLE2	NM_003260.5	MANE Select	c.2139C>T	p.Ser713Ser	synonymous	Exon 20 of 20	NP_003251.2
	TLE2	NM_001144761.2		c.2104C>T	p.Leu702Phe	missense	Exon 20 of 20	NP_001138233.1	Q04725-3
	TLE2	NM_001300846.2		c.2142C>T	p.Ser714Ser	synonymous	Exon 20 of 20	NP_001287775.1	K7EMK7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE2	ENST00000591529.5	TSL:1	c.2104C>T	p.Leu702Phe	missense	Exon 20 of 20	ENSP00000468279.1	Q04725-3
	TLE2	ENST00000262953.11	TSL:1 MANE Select	c.2139C>T	p.Ser713Ser	synonymous	Exon 20 of 20	ENSP00000262953.5	Q04725-1
	TLE2	ENST00000590536.5	TSL:1	c.2142C>T	p.Ser714Ser	synonymous	Exon 20 of 20	ENSP00000466542.1	K7EMK7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460022 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726136

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 85806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111140

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.8
DANN	Benign	0.92
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-0.99	T
PhyloP100		-1.4
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.029
Sift	Benign	0.031	D
Sift4G	Pathogenic	0.0	D
Vest4		0.14
MutPred		0.51		Gain of catalytic residue at L702 (P = 0.0273)
MVP		0.44
ClinPred		0.051	T
GERP RS		-0.98
Mutation Taster		=90/10	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: rs373620175; hg19: chr19-2997939;