NM_001367943.1:c.552+9017G>T

Variant names:

• chr10-113049143-G-T
• rs12255372
• NM_001367943.1:c.552+9017G>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.552+9017G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 151,804 control chromosomes in the GnomAD database, including 5,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency: Genomes: 𝑓 0.27 (5769 hom., cov: 31)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: -0.0150
• Publications: 462 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 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.552+9017G>T		intron	N/A	NP_001354872.1
	TCF7L2	NM_001146274.2		c.552+9017G>T		intron	N/A	NP_001139746.1
	TCF7L2	NM_030756.5		c.483+9017G>T		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.552+9017G>T		intron	N/A	ENSP00000348274.4
	TCF7L2	ENST00000627217.3	TSL:1	c.552+9017G>T		intron	N/A	ENSP00000486891.1
	TCF7L2	ENST00000369397.8	TSL:1	c.483+9017G>T		intron	N/A	ENSP00000358404.4

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40565 AN: 151686 Hom.: 5759 Cov.: 31

Gnomad AFR AF: 0.299

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.00967

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.267 AC: 40590 AN: 151804 Hom.: 5769 Cov.: 31 AF XY: 0.260 AC XY: 19259 AN XY: 74206

African (AFR) AF: 0.299 AC: 12351 AN: 41334

American (AMR) AF: 0.258 AC: 3935 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1090 AN: 3466

East Asian (EAS) AF: 0.00969 AC: 50 AN: 5158

South Asian (SAS) AF: 0.252 AC: 1213 AN: 4808

European-Finnish (FIN) AF: 0.159 AC: 1683 AN: 10560

Middle Eastern (MID) AF: 0.333 AC: 96 AN: 288

European-Non Finnish (NFE) AF: 0.283 AC: 19208 AN: 67938

Other (OTH) AF: 0.313 AC: 657 AN: 2100

Alfa AF: 0.278 Hom.: 21889

Bravo AF: 0.274

Asia WGS AF: 0.126 AC: 444 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Diabetes mellitus type 2, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.70
PhyloP100		-0.015
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: rs12255372; hg19: chr10-114808902;