10-112951522-C-T

Variant names:

• chr10-112951522-C-T
• rs753753787
• NM_001367943.1:c.296C>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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

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]

ENSG00000233547 (HGNC:):

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 rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.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
TCF7L2	ENST00000355995.9	c.296C>T	p.Pro99Leu	missense_variant	Exon 3 of 15	1	NM_001367943.1	ENSP00000348274.4

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

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

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

Other links and lift over

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