Genetic Variant NM_003260.5:c.2050C>T (chr19-3000721-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★). Synonymous variant affecting the same amino acid position (i.e. R684R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TLE2
NM_003260.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58

Publications

0 publications found

Variant links:

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]

TLE2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003260.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLE2	NM_003260.5	MANE Select	c.2050C>T	p.Arg684Trp	missense splice_region	Exon 19 of 20	NP_003251.2
TLE2	NM_001300846.2		c.2053C>T	p.Arg685Trp	missense splice_region	Exon 19 of 20	NP_001287775.1	K7EMK7
TLE2	NM_001144762.2		c.1684C>T	p.Arg562Trp	missense splice_region	Exon 17 of 18	NP_001138234.1	Q04725-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLE2	ENST00000262953.11	TSL:1 MANE Select	c.2050C>T	p.Arg684Trp	missense splice_region	Exon 19 of 20	ENSP00000262953.5	Q04725-1
TLE2	ENST00000590536.5	TSL:1	c.2053C>T	p.Arg685Trp	missense splice_region	Exon 19 of 20	ENSP00000466542.1	K7EMK7
TLE2	ENST00000591529.5	TSL:1	c.2089+1632C>T		intron	N/A	ENSP00000468279.1	Q04725-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000507

AC:

AN:

197316

AF XY:

0.00000944

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000175

AC:

AN:

1430960

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

708748

show subpopulations

African (AFR)

AF:

0.0000916

AC:

AN:

32760

American (AMR)

AF:

0.00

AC:

AN:

39820

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25542

East Asian (EAS)

AF:

0.00

AC:

AN:

38046

South Asian (SAS)

AF:

0.00

AC:

AN:

81506

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.0000201

AC:

AN:

1096916

Other (OTH)

AF:

0.00

AC:

AN:

59326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.098

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

4.6

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.24

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.63

MutPred

0.61

Loss of MoRF binding (P = 0.0588)

MVP

0.74

MPC

1.5

ClinPred

0.96

GERP RS

1.5

Varity_R

0.35

gMVP

0.65

Mutation Taster

=80/20

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over