Genetic Variant NM_001367943.1:c.296C>A (chr10-112951522-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001367943.1(TCF7L2):c.296C>A(p.Pro99Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCF7L2
NM_001367943.1 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided 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]

TCF7L2 links:

ENSG00000233547 (HGNC:):

ENSG00000233547 links:

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
TCF7L2	NM_001367943.1 link	c.296C>A	p.Pro99Gln	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 link	c.296C>A	p.Pro99Gln	missense_variant	Exon 3 of 15	1	NM_001367943.1	ENSP00000348274.4		Q9NQB0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1281122

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

637986

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TCF7L2-related disorder

Uncertain:1

Dec 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TCF7L2 c.296C>A variant is predicted to result in the amino acid substitution p.Pro99Gln. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.032

T;T;T;.;T;.;.;.;.;T;.;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;.;M;M;.;M;M;M;M;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.2

N;N;N;N;N;.;N;N;N;D;N;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0060

D;D;D;D;D;.;D;D;D;D;D;.;D

Sift4G

Benign

0.099

T;T;D;T;D;D;T;T;T;T;T;T;D

Polyphen

0.46, 0.25, 0.64

.;P;.;.;.;B;.;.;.;.;P;.;.

Vest4

0.44

MutPred

0.41

Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);Loss of glycosylation at P99 (P = 0.0665);.;

MVP

0.80

MPC

0.58

ClinPred

0.80

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.69

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over