rs1225404

Variant names:

• chr10-113154906-C-T
• rs1225404
• NM_001367943.1:c.1269+2466C>T

Variant summary

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

The NM_001367943.1(TCF7L2):​c.1269+2466C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 151,884 control chromosomes in the GnomAD database, including 39,403 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 0.71 (39403 hom., cov: 31)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.292
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.1269+2466C>T		intron_variant	Intron 11 of 14	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.1269+2466C>T		intron_variant	Intron 11 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108364 AN: 151766 Hom.: 39370 Cov.: 31

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.805

Gnomad EAS AF: 0.936

Gnomad SAS AF: 0.765

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.653

Gnomad OTH AF: 0.752

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

GnomAD4 genome AF: 0.714 AC: 108447 AN: 151884 Hom.: 39403 Cov.: 31 AF XY: 0.715 AC XY: 53100 AN XY: 74218

African (AFR) AF: 0.795 AC: 32925 AN: 41410

American (AMR) AF: 0.707 AC: 10805 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 2791 AN: 3468

East Asian (EAS) AF: 0.936 AC: 4820 AN: 5148

South Asian (SAS) AF: 0.764 AC: 3676 AN: 4810

European-Finnish (FIN) AF: 0.618 AC: 6490 AN: 10500

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.653 AC: 44396 AN: 67954

Other (OTH) AF: 0.752 AC: 1583 AN: 2106

Alfa AF: 0.679 Hom.: 74257

Bravo AF: 0.724

Asia WGS AF: 0.820 AC: 2855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.57
PhyloP100		-0.29
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: rs1225404; hg19: chr10-114914665;