NM_001367943.1:c.372delC

Variant names:

• chr10-112951596-AC-A
• NM_001367943.1:c.372delC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001367943.1(TCF7L2):​c.372delC​(p.Ala125ProfsTer30) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 27)
• Consequence: TCF7L2 NM_001367943.1 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.372delC	p.Ala125ProfsTer30	frameshift	Exon 3 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.372delC	p.Ala125ProfsTer30	frameshift	Exon 3 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.372delC	p.Ala125ProfsTer7	frameshift	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.372delC	p.Ala125ProfsTer30	frameshift	Exon 3 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.372delC	p.Ala125ProfsTer30	frameshift	Exon 3 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.372delC	p.Ala125ProfsTer7	frameshift	Exon 3 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 27

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr10-114711355;