chr19-2997945-G-A

Position:

• chr19-2997945-G-A

Variant summary

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

The NM_003260.5(TLE2):​c.2135C>T​(p.Ser712Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,458,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S712S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TLE2 NM_003260.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.94

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/exons	MANE	UniProt
TLE2	NM_003260.5	c.2135C>T	p.Ser712Leu	missense_variant	20/20	ENST00000262953.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLE2	ENST00000262953.11	c.2135C>T	p.Ser712Leu	missense_variant	20/20	1	NM_003260.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1458600 Hom.: 0 Cov.: 30 AF XY: 0.0000248 AC XY: 18 AN XY: 725380

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.2135C>T (p.S712L) alteration is located in exon 20 (coding exon 20) of the TLE2 gene. This alteration results from a C to T substitution at nucleotide position 2135, causing the serine (S) at amino acid position 712 to be replaced by a leucine (L). 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	0.19
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.2	D;D;D;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.67
MVP		0.89
MPC		1.4
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.75
gMVP		0.49

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: rs371891336; hg19: chr19-2997943;