10-112951635-C-T

Variant names:

• chr10-112951635-C-T
• rs555488416
• NM_001367943.1:c.381+28C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001367943.1(TCF7L2):​c.381+28C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000362 in 1,104,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000070 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.129
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

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.381+28C>T		intron	N/A	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.381+28C>T		intron	N/A	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.381+28C>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.381+28C>T		intron	N/A	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.381+28C>T		intron	N/A	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.381+28C>T		intron	N/A	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.00000703 AC: 1 AN: 142152 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000312 AC: 3 AN: 962074 Hom.: 0 Cov.: 30 AF XY: 0.00000217 AC XY: 1 AN XY: 461058

African (AFR) AF: 0.00 AC: 0 AN: 18212

American (AMR) AF: 0.00 AC: 0 AN: 4396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8642

East Asian (EAS) AF: 0.00 AC: 0 AN: 9888

South Asian (SAS) AF: 0.00 AC: 0 AN: 24656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2730

European-Non Finnish (NFE) AF: 0.00000239 AC: 2 AN: 836354

Other (OTH) AF: 0.0000301 AC: 1 AN: 33262

GnomAD4 genome AF: 0.00000703 AC: 1 AN: 142152 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 69118

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000262 AC: 1 AN: 38176

American (AMR) AF: 0.00 AC: 0 AN: 14564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3348

East Asian (EAS) AF: 0.00 AC: 0 AN: 4758

South Asian (SAS) AF: 0.00 AC: 0 AN: 4544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64854

Other (OTH) AF: 0.00 AC: 0 AN: 1948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	16
DANN	Benign	0.95
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs555488416; hg19: chr10-114711394;