chr10-112950801-C-T

Variant names:

• chr10-112950801-C-T
• rs76088094
• NM_001367943.1:c.45C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001367943.1(TCF7L2):​c.45C>T​(p.Asn15Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.00198 in 1,593,186 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 29)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: TCF7L2 NM_001367943.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.30
• Publications: 5 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

ENSG00000233547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 10-112950801-C-T is Benign according to our data. Variant chr10-112950801-C-T is described in ClinVar as Benign. ClinVar VariationId is 780893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1582/151888) while in subpopulation AFR AF = 0.0357 (1478/41392). AF 95% confidence interval is 0.0342. There are 30 homozygotes in GnomAd4. There are 733 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1582 AD,Unknown gene.

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.45C>T	p.Asn15Asn	synonymous	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.45C>T	p.Asn15Asn	synonymous	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.45C>T	p.Asn15Asn	synonymous	Exon 1 of 14	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.45C>T	p.Asn15Asn	synonymous	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.45C>T	p.Asn15Asn	synonymous	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.45C>T	p.Asn15Asn	synonymous	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1580 AN: 151772 Hom.: 30 Cov.: 29

Gnomad AFR AF: 0.0357

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00671

GnomAD2 exomes AF: 0.00257 AC: 565 AN: 219846 AF XY: 0.00195

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000543

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00144

GnomAD4 exome AF: 0.00110 AC: 1579 AN: 1441298 Hom.: 24 Cov.: 32 AF XY: 0.000919 AC XY: 657 AN XY: 714734

African (AFR) AF: 0.0370 AC: 1232 AN: 33290

American (AMR) AF: 0.00192 AC: 81 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.000782 AC: 20 AN: 25560

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.000144 AC: 12 AN: 83546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51882

Middle Eastern (MID) AF: 0.00193 AC: 10 AN: 5192

European-Non Finnish (NFE) AF: 0.0000909 AC: 100 AN: 1100502

Other (OTH) AF: 0.00208 AC: 124 AN: 59610

GnomAD4 genome AF: 0.0104 AC: 1582 AN: 151888 Hom.: 30 Cov.: 29 AF XY: 0.00988 AC XY: 733 AN XY: 74210

African (AFR) AF: 0.0357 AC: 1478 AN: 41392

American (AMR) AF: 0.00531 AC: 81 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67990

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00442 Hom.: 7

Bravo AF: 0.0122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		4.3
PromoterAI		0.096	Neutral
Mutation Taster		=200/100	polymorphism

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: rs76088094; hg19: chr10-114710560;