Genetic Variant TCF7L2:c.450+33966C>T (chr10-112998590-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001367943.1(TCF7L2):c.450+33966C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,914 control chromosomes in the GnomAD database, including 5,952 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: 𝑓 0.27 ( 5952 hom., cov: 32)

Consequence

TCF7L2
NM_001367943.1 intron

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 0.133

Publications

1629 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 Submitted by: G2P
intellectual disability
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
congenital glaucoma
Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

TCF7L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1 link	c.450+33966C>T		intron_variant	Intron 4 of 14	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9 link	c.450+33966C>T		intron_variant	Intron 4 of 14	1	NM_001367943.1	ENSP00000348274.4		Q9NQB0-1

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41569

AN:

151796

Hom.:

5936

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.265

Gnomad ASJ

AF:

0.287

Gnomad EAS

AF:

0.0268

Gnomad SAS

AF:

0.304

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.321

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.274

AC:

41622

AN:

151914

Hom.:

5952

Cov.:

AF XY:

0.269

AC XY:

19967

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.293

AC:

12132

AN:

41386

American (AMR)

AF:

0.265

AC:

4044

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.287

AC:

995

AN:

3466

East Asian (EAS)

AF:

0.0269

AC:

139

AN:

5172

South Asian (SAS)

AF:

0.304

AC:

1467

AN:

4822

European-Finnish (FIN)

AF:

0.188

AC:

1982

AN:

10540

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.292

AC:

19833

AN:

67952

Other (OTH)

AF:

0.317

AC:

668

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1525

3050

4575

6100

7625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.284

Hom.:

28306

Bravo

AF:

0.277

Asia WGS

AF:

0.156

AC:

552

AN:

3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Diabetes mellitus type 2, susceptibility to

Other:1

Sep 01, 2011

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

4.1

(source)

DANN

Benign

0.59

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over