10-112951514-G-C

Variant names:

• chr10-112951514-G-C
• rs766204038
• NM_001367943.1:c.288G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001367943.1(TCF7L2):​c.288G>C​(p.Lys96Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000234 in 1,282,112 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.288G>C	p.Lys96Asn	missense	Exon 3 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.288G>C	p.Lys96Asn	missense	Exon 3 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.288G>C	p.Lys96Asn	missense	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.288G>C	p.Lys96Asn	missense	Exon 3 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.288G>C	p.Lys96Asn	missense	Exon 3 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.288G>C	p.Lys96Asn	missense	Exon 3 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000234 AC: 3 AN: 1282112 Hom.: 0 Cov.: 32 AF XY: 0.00000157 AC XY: 1 AN XY: 638580

African (AFR) AF: 0.00 AC: 0 AN: 25500

American (AMR) AF: 0.00 AC: 0 AN: 33654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19312

East Asian (EAS) AF: 0.00 AC: 0 AN: 23666

South Asian (SAS) AF: 0.00 AC: 0 AN: 78560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4878

European-Non Finnish (NFE) AF: 0.00000299 AC: 3 AN: 1002828

Other (OTH) AF: 0.00 AC: 0 AN: 48754

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.14	T
Polyphen		0.15	B
Vest4		0.59
MutPred		0.50		Loss of methylation at K96 (P = 0)
MVP		0.94
MPC		0.85
ClinPred		0.97	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.48
Mutation Taster		=63/37	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: rs766204038; hg19: chr10-114711273;