rs12245680

Variant names:

• chr10-113060432-T-C
• rs12245680
• NM_001367943.1:c.552+20306T>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.552+20306T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0865 in 152,204 control chromosomes in the GnomAD database, including 574 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 0.087 (574 hom., cov: 32)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.104
• Publications: 10 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.552+20306T>C		intron_variant	Intron 5 of 14	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.552+20306T>C		intron_variant	Intron 5 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 13174 AN: 152086 Hom.: 574 Cov.: 32

Gnomad AFR AF: 0.0787

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.00908

Gnomad SAS AF: 0.0576

Gnomad FIN AF: 0.0744

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.0932

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

GnomAD4 genome AF: 0.0865 AC: 13172 AN: 152204 Hom.: 574 Cov.: 32 AF XY: 0.0852 AC XY: 6339 AN XY: 74406

African (AFR) AF: 0.0785 AC: 3259 AN: 41522

American (AMR) AF: 0.0853 AC: 1305 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.00910 AC: 47 AN: 5164

South Asian (SAS) AF: 0.0580 AC: 280 AN: 4826

European-Finnish (FIN) AF: 0.0744 AC: 788 AN: 10598

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0994 AC: 6761 AN: 68004

Other (OTH) AF: 0.0927 AC: 196 AN: 2114

Alfa AF: 0.0930 Hom.: 803

Bravo AF: 0.0860

Asia WGS AF: 0.0450 AC: 158 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.6
DANN	Benign	0.39
PhyloP100		-0.10
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: rs12245680; hg19: chr10-114820191;