chr10-112951574-C-T

Variant names:

• chr10-112951574-C-T
• rs143305771
• NM_001367943.1:c.348C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001367943.1(TCF7L2):​c.348C>T​(p.Leu116Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,372,036 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0024 (10 hom.)
• Consequence: TCF7L2 NM_001367943.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.112
• 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

ENSG00000233547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 10-112951574-C-T is Benign according to our data. Variant chr10-112951574-C-T is described in ClinVar as Benign. ClinVar VariationId is 770593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.112 with no splicing effect.
• BS2: High AC in GnomAd4 at 284 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.348C>T	p.Leu116Leu	synonymous	Exon 3 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.348C>T	p.Leu116Leu	synonymous	Exon 3 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.348C>T	p.Leu116Leu	synonymous	Exon 3 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.348C>T	p.Leu116Leu	synonymous	Exon 3 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.348C>T	p.Leu116Leu	synonymous	Exon 3 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.348C>T	p.Leu116Leu	synonymous	Exon 3 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.00192 AC: 285 AN: 148218 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00475

Gnomad ASJ AF: 0.00441

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00669

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0132

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00293

GnomAD2 exomes AF: 0.00246 AC: 460 AN: 187140 AF XY: 0.00299

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00364

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00241 AC: 2947 AN: 1223710 Hom.: 10 Cov.: 32 AF XY: 0.00259 AC XY: 1576 AN XY: 608890

African (AFR) AF: 0.000286 AC: 7 AN: 24436

American (AMR) AF: 0.00233 AC: 71 AN: 30506

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 71 AN: 17576

East Asian (EAS) AF: 0.00 AC: 0 AN: 20446

South Asian (SAS) AF: 0.00716 AC: 514 AN: 71746

European-Finnish (FIN) AF: 0.0000482 AC: 2 AN: 41476

Middle Eastern (MID) AF: 0.0102 AC: 47 AN: 4616

European-Non Finnish (NFE) AF: 0.00218 AC: 2108 AN: 967902

Other (OTH) AF: 0.00282 AC: 127 AN: 45006

GnomAD4 genome AF: 0.00191 AC: 284 AN: 148326 Hom.: 1 Cov.: 29 AF XY: 0.00178 AC XY: 129 AN XY: 72298

African (AFR) AF: 0.000341 AC: 14 AN: 41078

American (AMR) AF: 0.00475 AC: 71 AN: 14954

Ashkenazi Jewish (ASJ) AF: 0.00441 AC: 15 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5036

South Asian (SAS) AF: 0.00649 AC: 31 AN: 4776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9366

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.00215 AC: 143 AN: 66452

Other (OTH) AF: 0.00290 AC: 6 AN: 2066

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00208

Asia WGS AF: 0.00214 AC: 7 AN: 3284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		-0.11
Mutation Taster		=97/3	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: rs143305771; hg19: chr10-114711333;