rs373536721

Variant names:

• chr10-112951217-G-A
• rs373536721
• NM_001367943.1:c.200G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-112951217-G-A
• chr10-112951217-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001367943.1(TCF7L2):​c.200G>A​(p.Arg67Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000209 in 1,433,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32472366).

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.200G>A	p.Arg67Gln	missense	Exon 2 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.200G>A	p.Arg67Gln	missense	Exon 2 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.200G>A	p.Arg67Gln	missense	Exon 2 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.200G>A	p.Arg67Gln	missense	Exon 2 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.200G>A	p.Arg67Gln	missense	Exon 2 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.200G>A	p.Arg67Gln	missense	Exon 2 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.00000476 AC: 1 AN: 210076 AF XY: 0.00000858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433798 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 712798

African (AFR) AF: 0.00 AC: 0 AN: 31492

American (AMR) AF: 0.00 AC: 0 AN: 41006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25338

East Asian (EAS) AF: 0.00 AC: 0 AN: 36172

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1100660

Other (OTH) AF: 0.00 AC: 0 AN: 59016

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000166 AC: 2

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
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.64	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.32	T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.2	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.50
Sift	Benign	0.17	T
Sift4G	Benign	0.42	T
Polyphen		0.49	P
Vest4		0.25
MVP		0.85
MPC		1.2
ClinPred		0.31	T
GERP RS		1.8
PromoterAI		-0.087	Neutral
Varity_R		0.15
gMVP		0.46
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs373536721; hg19: chr10-114710976;