Genetic Variant TCF7L2:p.Glu28Gln (chr10-112950838-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001367943.1(TCF7L2):c.82G>C(p.Glu28Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. E28D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 29)

Consequence

TCF7L2
NM_001367943.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.14

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
intellectual disability
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
congenital glaucoma
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

TCF7L2 links:

ENSG00000233547 (HGNC:):

ENSG00000233547 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3461346).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367943.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	NM_001367943.1	MANE Select	c.82G>C	p.Glu28Gln	missense	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
TCF7L2	NM_001146274.2		c.82G>C	p.Glu28Gln	missense	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
TCF7L2	NM_030756.5		c.82G>C	p.Glu28Gln	missense	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.82G>C	p.Glu28Gln	missense	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
TCF7L2	ENST00000627217.3	TSL:1	c.82G>C	p.Glu28Gln	missense	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
TCF7L2	ENST00000369397.8	TSL:1	c.82G>C	p.Glu28Gln	missense	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.034

Eigen

Benign

-0.014

Eigen_PC

Benign

0.070

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.35

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

PhyloP100

7.1

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.54

Sift

Benign

0.22

Sift4G

Benign

0.11

Polyphen

0.12

Vest4

0.37

MutPred

0.37

Loss of solvent accessibility (P = 0.0721)

MVP

0.84

MPC

1.6

ClinPred

0.94

GERP RS

3.1

PromoterAI

-0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.31

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over