19-3006584-G-C

Variant names:

• chr19-3006584-G-C
• rs369405404
• NM_003260.5:c.1336C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003260.5(TLE2):​c.1336C>G​(p.Arg446Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R446W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TLE2 NM_003260.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE2	NM_003260.5	MANE Select	c.1336C>G	p.Arg446Gly	missense	Exon 15 of 20	NP_003251.2
	TLE2	NM_001300846.2		c.1339C>G	p.Arg447Gly	missense	Exon 15 of 20	NP_001287775.1	K7EMK7
	TLE2	NM_001144761.2		c.1378C>G	p.Arg460Gly	missense	Exon 16 of 20	NP_001138233.1	Q04725-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLE2	ENST00000262953.11	TSL:1 MANE Select	c.1336C>G	p.Arg446Gly	missense	Exon 15 of 20	ENSP00000262953.5	Q04725-1
	TLE2	ENST00000590536.5	TSL:1	c.1339C>G	p.Arg447Gly	missense	Exon 15 of 20	ENSP00000466542.1	K7EMK7
	TLE2	ENST00000591529.5	TSL:1	c.1378C>G	p.Arg460Gly	missense	Exon 16 of 20	ENSP00000468279.1	Q04725-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453956 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722732

African (AFR) AF: 0.00 AC: 0 AN: 33304

American (AMR) AF: 0.00 AC: 0 AN: 43784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 85080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51738

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109284

Other (OTH) AF: 0.00 AC: 0 AN: 59996

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.49		Loss of solvent accessibility (P = 0.0092)
MVP		0.70
MPC		1.5
ClinPred		1.0	D
GERP RS		2.7
Varity_R		0.75
gMVP		0.50
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs369405404; hg19: chr19-3006582; COSMIC: COSV53579846; COSMIC: COSV53579846;