10-112993500-T-C

Variant names:

• chr10-112993500-T-C
• rs61875120
• NM_001367943.1:c.450+28876T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367943.1(TCF7L2):​c.450+28876T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 151,924 control chromosomes in the GnomAD database, including 2,669 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2669 hom., cov: 31)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 4 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.450+28876T>C		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	c.450+28876T>C		intron_variant	Intron 4 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25657 AN: 151806 Hom.: 2664 Cov.: 31

Gnomad AFR AF: 0.0638

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.224

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

GnomAD4 genome AF: 0.169 AC: 25673 AN: 151924 Hom.: 2669 Cov.: 31 AF XY: 0.167 AC XY: 12415 AN XY: 74248

African (AFR) AF: 0.0639 AC: 2650 AN: 41464

American (AMR) AF: 0.196 AC: 2987 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3470

East Asian (EAS) AF: 0.0188 AC: 97 AN: 5168

South Asian (SAS) AF: 0.252 AC: 1208 AN: 4802

European-Finnish (FIN) AF: 0.159 AC: 1670 AN: 10522

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15526 AN: 67906

Other (OTH) AF: 0.222 AC: 469 AN: 2114

Alfa AF: 0.189 Hom.: 3919

Bravo AF: 0.164

Asia WGS AF: 0.104 AC: 364 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.15
DANN	Benign	0.19
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61875120; hg19: chr10-114753259;