10-112955930-C-T

Variant names:

• chr10-112955930-C-T
• rs2094405
• NM_001367943.1:c.381+4323C>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.381+4323C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 151,258 control chromosomes in the GnomAD database, including 11,566 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 0.37 (11566 hom., cov: 30)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 9 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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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.381+4323C>T		intron	N/A	NP_001354872.1
	TCF7L2	NM_001146274.2		c.381+4323C>T		intron	N/A	NP_001139746.1
	TCF7L2	NM_030756.5		c.381+4323C>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.381+4323C>T		intron	N/A	ENSP00000348274.4
	TCF7L2	ENST00000627217.3	TSL:1	c.381+4323C>T		intron	N/A	ENSP00000486891.1
	TCF7L2	ENST00000369397.8	TSL:1	c.381+4323C>T		intron	N/A	ENSP00000358404.4

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55372 AN: 151140 Hom.: 11546 Cov.: 30

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.209

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.372

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

GnomAD4 genome AF: 0.366 AC: 55424 AN: 151258 Hom.: 11566 Cov.: 30 AF XY: 0.361 AC XY: 26664 AN XY: 73780

African (AFR) AF: 0.584 AC: 24060 AN: 41228

American (AMR) AF: 0.335 AC: 5063 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1223 AN: 3464

East Asian (EAS) AF: 0.324 AC: 1658 AN: 5122

South Asian (SAS) AF: 0.310 AC: 1489 AN: 4798

European-Finnish (FIN) AF: 0.209 AC: 2154 AN: 10324

Middle Eastern (MID) AF: 0.362 AC: 105 AN: 290

European-Non Finnish (NFE) AF: 0.275 AC: 18654 AN: 67890

Other (OTH) AF: 0.369 AC: 776 AN: 2102

Alfa AF: 0.281 Hom.: 6413

Bravo AF: 0.385

Asia WGS AF: 0.277 AC: 962 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.84
PhyloP100		1.1
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: rs2094405; hg19: chr10-114715689;