chr10-112950840-G-C

Position:

chr10-112950840-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The ENST00000355995.9(TCF7L2):c.84G>C(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,608,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. E28Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TCF7L2
ENST00000355995.9 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.01

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a mutagenesis_site Abolishes CTNNB1 binding; when associated with A-24; A-26 and A-29. (size 0) in uniprot entity TF7L2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.22029236).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7L2	NM_001367943.1 linkuse as main transcript	c.84G>C	p.Glu28Asp	missense_variant	1/15	ENST00000355995.9	NP_001354872.1
LOC124902502	XR_007062291.1 linkuse as main transcript	n.733C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9 linkuse as main transcript	c.84G>C	p.Glu28Asp	missense_variant	1/15	1	NM_001367943.1	ENSP00000348274		Q9NQB0-1
	ENST00000369391.3 linkuse as main transcript	n.266C>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000413

AC:

AN:

242200

Hom.:

AF XY:

0.0000459

AC XY:

AN XY:

130828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

217

AN:

1456210

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

723818

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000187

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The TCF7L2 p.E28D variant was not identified in the literature nor was it identified in ClinVar, Cosmic, or LOVD 3.0. The variant was identified in dbSNP (ID: rs373425129) and in control databases in 10 of 242200 chromosomes at a frequency of 0.000041 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 10 of 109400 chromosomes (freq: 0.000091), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Glu28 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.035

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

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.22

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.5

.;.;L;L;.;L;L;L;L;.;.;.

MutationTaster

Benign

0.92

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

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.8

N;N;N;N;N;.;N;N;N;N;N;.

REVEL

Uncertain

0.47

Sift

Benign

0.046

D;D;D;D;D;.;T;D;T;T;D;.

Sift4G

Benign

0.11

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

Polyphen

0.011, 0.022, 0.0080

.;B;.;.;.;B;.;.;.;.;B;.

Vest4

0.33

MutPred

0.33

Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);Loss of solvent accessibility (P = 0.1177);

MVP

0.83

MPC

0.69

ClinPred

0.25

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.18

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over