rs10749127

Variant names:

• chr10-113089594-C-T
• rs10749127
• NM_001367943.1:c.552+49468C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367943.1(TCF7L2):​c.552+49468C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,589,330 control chromosomes in the GnomAD database, including 67,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6088 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61045 hom.)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.719
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-113089594-C-T is Benign according to our data. Variant chr10-113089594-C-T is described in ClinVar as [Benign]. Clinvar id is 1267768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.552+49468C>T		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+49468C>T		intron_variant	Intron 5 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42680 AN: 151910 Hom.: 6083 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.323

Gnomad FIN AF: 0.266

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.290 AC: 416240 AN: 1437300 Hom.: 61045 AF XY: 0.291 AC XY: 207705 AN XY: 713038

African (AFR) AF: 0.242 AC: 7886 AN: 32626

American (AMR) AF: 0.288 AC: 12043 AN: 41760

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8154 AN: 24676

East Asian (EAS) AF: 0.246 AC: 9662 AN: 39228

South Asian (SAS) AF: 0.325 AC: 26740 AN: 82160

European-Finnish (FIN) AF: 0.274 AC: 14381 AN: 52560

Middle Eastern (MID) AF: 0.328 AC: 1767 AN: 5388

European-Non Finnish (NFE) AF: 0.289 AC: 318161 AN: 1099660

Other (OTH) AF: 0.294 AC: 17446 AN: 59242

GnomAD4 genome AF: 0.281 AC: 42703 AN: 152030 Hom.: 6088 Cov.: 32 AF XY: 0.282 AC XY: 20953 AN XY: 74308

African (AFR) AF: 0.240 AC: 9962 AN: 41464

American (AMR) AF: 0.321 AC: 4896 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1123 AN: 3468

East Asian (EAS) AF: 0.280 AC: 1448 AN: 5164

South Asian (SAS) AF: 0.324 AC: 1561 AN: 4816

European-Finnish (FIN) AF: 0.266 AC: 2809 AN: 10570

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19893 AN: 67972

Other (OTH) AF: 0.308 AC: 649 AN: 2108

Alfa AF: 0.294 Hom.: 10997

Bravo AF: 0.279

Asia WGS AF: 0.308 AC: 1069 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		0.72
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: rs10749127; hg19: chr10-114849353; COSMIC: COSV60501258;