rs6585205

Variant names:

• chr10-113099405-G-T
• rs6585205
• NM_001367943.1:c.553-41779G>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.553-41779G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 152,004 control chromosomes in the GnomAD database, including 39,209 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 0.71 (39209 hom., cov: 31)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 6 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, STRONG Submitted by: G2P, PanelApp Australia
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.793 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	NM_001367943.1	MANE Select	c.553-41779G>T		intron	N/A	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.553-41779G>T		intron	N/A	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.484-41779G>T		intron	N/A	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.553-41779G>T		intron	N/A	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.553-41779G>T		intron	N/A	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.484-41779G>T		intron	N/A	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.714 AC: 108441 AN: 151886 Hom.: 39159 Cov.: 31

Gnomad AFR AF: 0.800

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.447

Gnomad SAS AF: 0.575

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.706

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

GnomAD4 genome AF: 0.714 AC: 108548 AN: 152004 Hom.: 39209 Cov.: 31 AF XY: 0.712 AC XY: 52872 AN XY: 74278

African (AFR) AF: 0.800 AC: 33188 AN: 41474

American (AMR) AF: 0.742 AC: 11339 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2556 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2303 AN: 5148

South Asian (SAS) AF: 0.576 AC: 2775 AN: 4818

European-Finnish (FIN) AF: 0.705 AC: 7441 AN: 10548

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.685 AC: 46562 AN: 67950

Other (OTH) AF: 0.700 AC: 1476 AN: 2108

Alfa AF: 0.692 Hom.: 12394

Bravo AF: 0.719

Asia WGS AF: 0.538 AC: 1873 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.042
DANN	Benign	0.59
PhyloP100		-2.1
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: rs6585205; hg19: chr10-114859164; COSMIC: COSV60501672;