10-112951522-C-T

Variant summary

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

The NM_001367943.1(TCF7L2):​c.296C>T​(p.Pro99Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000156 in 1,281,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

TCF7L2
NM_001367943.1 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.60
Variant links:
Genes affected
TCF7L2 (HGNC:11641): (transcription factor 7 like 2) This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
TCF7L2NM_001367943.1 linkc.296C>T p.Pro99Leu missense_variant Exon 3 of 15 ENST00000355995.9 NP_001354872.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCF7L2ENST00000355995.9 linkc.296C>T p.Pro99Leu missense_variant Exon 3 of 15 1 NM_001367943.1 ENSP00000348274.4 Q9NQB0-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
0.00000156
AC:
2
AN:
1281124
Hom.:
0
Cov.:
32
AF XY:
0.00000313
AC XY:
2
AN XY:
637988
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000596
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
29
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Jul 09, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.035
T;T;T;.;T;.;.;.;.;T;.;T;T
Eigen
Benign
-0.46
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.34
N
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Uncertain
0.53
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Benign
1.8
.;.;L;L;.;L;L;L;L;.;.;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Uncertain
-3.0
D;D;D;D;D;.;D;D;D;D;D;.;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0040
D;D;D;D;D;.;D;D;T;D;D;.;D
Sift4G
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen
0.28, 0.010, 0.0050
.;B;.;.;.;B;.;.;.;.;B;.;.
Vest4
0.41
MutPred
0.51
Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);Loss of disorder (P = 0.023);.;
MVP
0.63
MPC
0.63
ClinPred
0.71
D
GERP RS
2.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.27
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs753753787; hg19: chr10-114711281; COSMIC: COSV60501459; API