10-112951918-C-T

Variant names:

• chr10-112951918-C-T
• rs113999985
• NM_001367943.1:c.381+311C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367943.1(TCF7L2):​c.381+311C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 151,218 control chromosomes in the GnomAD database, including 24,101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (24024 hom., cov: 27)
  • Exomes 𝑓: 0.44 (77 hom.)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.466
• 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

LOC124902502 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 10-112951918-C-T is Benign according to our data. Variant chr10-112951918-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

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+311C>T		intron	N/A	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.381+311C>T		intron	N/A	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.381+311C>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+311C>T		intron	N/A	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.381+311C>T		intron	N/A	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.381+311C>T		intron	N/A	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.562 AC: 84545 AN: 150470 Hom.: 23997 Cov.: 27

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.455

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.580

GnomAD4 exome AF: 0.443 AC: 279 AN: 630 Hom.: 77 Cov.: 0 AF XY: 0.484 AC XY: 206 AN XY: 426

African (AFR) AF: 0.542 AC: 13 AN: 24

American (AMR) AF: 0.455 AC: 10 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 4 AN: 6

East Asian (EAS) AF: 0.139 AC: 5 AN: 36

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

European-Finnish (FIN) AF: 0.348 AC: 16 AN: 46

Middle Eastern (MID) AF: 0.500 AC: 2 AN: 4

European-Non Finnish (NFE) AF: 0.462 AC: 208 AN: 450

Other (OTH) AF: 0.526 AC: 20 AN: 38

GnomAD4 genome AF: 0.562 AC: 84620 AN: 150588 Hom.: 24024 Cov.: 27 AF XY: 0.556 AC XY: 40854 AN XY: 73508

African (AFR) AF: 0.645 AC: 26374 AN: 40912

American (AMR) AF: 0.592 AC: 8989 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1926 AN: 3454

East Asian (EAS) AF: 0.385 AC: 1938 AN: 5036

South Asian (SAS) AF: 0.497 AC: 2371 AN: 4768

European-Finnish (FIN) AF: 0.455 AC: 4691 AN: 10310

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.538 AC: 36407 AN: 67628

Other (OTH) AF: 0.577 AC: 1209 AN: 2096

Alfa AF: 0.541 Hom.: 28746

Bravo AF: 0.572

Asia WGS AF: 0.433 AC: 1498 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs113999985; hg19: chr10-114711677; COSMIC: COSV60507102; COSMIC: COSV60507102;