Genetic Variant TCF7L2:c.381+10T>C (chr10-112951617-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001367943.1(TCF7L2):c.381+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000017 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCF7L2
NM_001367943.1 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.356

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 10-112951617-T-C is Benign according to our data. Variant chr10-112951617-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 735898.Status of the report is criteria_provided_single_submitter, 1 stars.

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	Effect	Exon Rank	Protein	UniProt
TCF7L2	NM_001367943.1	MANE Select	c.381+10T>C	intron	N/A	NP_001354872.1	Q9NQB0-1
TCF7L2	NM_001146274.2		c.381+10T>C	intron	N/A	NP_001139746.1	Q9NQB0-7
TCF7L2	NM_030756.5		c.381+10T>C	intron	N/A	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.381+10T>C	intron	N/A	ENSP00000348274.4	Q9NQB0-1
TCF7L2	ENST00000627217.3	TSL:1	c.381+10T>C	intron	N/A	ENSP00000486891.1	Q9NQB0-7
TCF7L2	ENST00000369397.8	TSL:1	c.381+10T>C	intron	N/A	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes

AF:

0.0000169

AC:

AN:

118286

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000665

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1073398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

524680

African (AFR)

AF:

0.00

AC:

AN:

21648

American (AMR)

AF:

0.00

AC:

AN:

20602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13908

East Asian (EAS)

AF:

0.00

AC:

AN:

12836

South Asian (SAS)

AF:

0.00

AC:

AN:

46740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3948

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

886328

Other (OTH)

AF:

0.00

AC:

AN:

38038

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000169

AC:

AN:

118286

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

56918

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000665

AC:

AN:

30090

American (AMR)

AF:

0.00

AC:

AN:

12116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2960

East Asian (EAS)

AF:

0.00

AC:

AN:

4068

South Asian (SAS)

AF:

0.00

AC:

AN:

3586

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56792

Other (OTH)

AF:

0.00

AC:

AN:

1590

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000037155), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions

Significance:Likely benign

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

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.37

PhyloP100

-0.36

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over