dbSNP rs76088094: TCF7L2:p.Asn15Lys (chr10-112950801-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001367943.1(TCF7L2):c.45C>A(p.Asn15Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N15N) has been classified as Benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCF7L2
NM_001367943.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.30

Publications

5 publications found

Variant links:

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

TCF7L2 links:

ENSG00000233547 (HGNC:):

ENSG00000233547 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	NM_001367943.1	MANE Select	c.45C>A	p.Asn15Lys	missense	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
TCF7L2	NM_001146274.2		c.45C>A	p.Asn15Lys	missense	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
TCF7L2	NM_030756.5		c.45C>A	p.Asn15Lys	missense	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.45C>A	p.Asn15Lys	missense	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
TCF7L2	ENST00000627217.3	TSL:1	c.45C>A	p.Asn15Lys	missense	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
TCF7L2	ENST00000369397.8	TSL:1	c.45C>A	p.Asn15Lys	missense	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441306

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714738

African (AFR)

AF:

0.00

AC:

AN:

33296

American (AMR)

AF:

0.00

AC:

AN:

42212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25560

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.00

AC:

AN:

83546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100502

Other (OTH)

AF:

0.00

AC:

AN:

59612

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.089

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.69

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

PhyloP100

4.3

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0080

Sift4G

Benign

0.065

Polyphen

0.98

Vest4

0.45

MutPred

0.51

Gain of ubiquitination at N15 (P = 0.0039)

MVP

0.95

MPC

1.7

ClinPred

0.99

GERP RS

3.5

PromoterAI

-0.069

Neutral

(source)

Varity_R

0.85

gMVP

0.47

Mutation Taster

=200/100

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over