10-113120583-T-C

Variant names:

• chr10-113120583-T-C
• rs4918796
• NM_001367943.1:c.553-20601T>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.553-20601T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,146 control chromosomes in the GnomAD database, including 2,958 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 0.18 (2958 hom., cov: 32)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 15 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=-0.99).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	NM_001367943.1	MANE Select	c.553-20601T>C		intron	N/A	NP_001354872.1
	TCF7L2	NM_001146274.2		c.553-20601T>C		intron	N/A	NP_001139746.1
	TCF7L2	NM_030756.5		c.484-20601T>C		intron	N/A	NP_110383.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.553-20601T>C		intron	N/A	ENSP00000348274.4
	TCF7L2	ENST00000627217.3	TSL:1	c.553-20601T>C		intron	N/A	ENSP00000486891.1
	TCF7L2	ENST00000369397.8	TSL:1	c.484-20601T>C		intron	N/A	ENSP00000358404.4

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27769 AN: 152028 Hom.: 2960 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.228

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

GnomAD4 genome AF: 0.183 AC: 27771 AN: 152146 Hom.: 2958 Cov.: 32 AF XY: 0.180 AC XY: 13424 AN XY: 74402

African (AFR) AF: 0.107 AC: 4452 AN: 41522

American (AMR) AF: 0.210 AC: 3213 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 945 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5186

South Asian (SAS) AF: 0.133 AC: 642 AN: 4814

European-Finnish (FIN) AF: 0.181 AC: 1915 AN: 10580

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.232 AC: 15803 AN: 67972

Other (OTH) AF: 0.225 AC: 475 AN: 2114

Alfa AF: 0.191 Hom.: 653

Bravo AF: 0.180

Asia WGS AF: 0.0770 AC: 269 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.5
DANN	Benign	0.53
PhyloP100		0.056
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: rs4918796; hg19: chr10-114880342;