rs2229470

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004613.4(TGM2):c.1170G>A(p.Ala390Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,614,164 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0069 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 95 hom. )

Consequence

TGM2
NM_004613.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.36

Publications

9 publications found

Variant links:

Genes affected

TGM2 (HGNC:11778): (transglutaminase 2) Transglutaminases are enzymes that catalyze the crosslinking of proteins by epsilon-gamma glutamyl lysine isopeptide bonds. While the primary structure of transglutaminases is not conserved, they all have the same amino acid sequence at their active sites and their activity is calcium-dependent. The protein encoded by this gene acts as a monomer, is induced by retinoic acid, and appears to be involved in apoptosis. Finally, the encoded protein is the autoantigen implicated in celiac disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TGM2 Gene-Disease associations (from GenCC):

type 2 diabetes mellitus
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TGM2 links:

ENSG00000293724 (HGNC:):

ENSG00000293724 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 20-38139584-C-T is Benign according to our data. Variant chr20-38139584-C-T is described in ClinVar as Benign. ClinVar VariationId is 770468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00842 (12302/1461892) while in subpopulation MID AF = 0.0307 (177/5768). AF 95% confidence interval is 0.027. There are 95 homozygotes in GnomAdExome4. There are 6274 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4 link	c.1170G>A	p.Ala390Ala	synonymous_variant	Exon 9 of 13	ENST00000361475.7	NP_004604.2	P21980-1V9HWG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGM2	ENST00000361475.7 link	c.1170G>A	p.Ala390Ala	synonymous_variant	Exon 9 of 13	1	NM_004613.4	ENSP00000355330.2	P21980-1
TGM2	ENST00000468262.5 link	n.1254G>A		non_coding_transcript_exon_variant	Exon 9 of 10	1
ENSG00000293724	ENST00000718567.1 link	n.121C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00696

AC:

1059

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00923

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00867

AC:

2181

AN:

251448

AF XY:

0.00909

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00555

Gnomad ASJ exome

AF:

0.0390

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00203

Gnomad NFE exome

AF:

0.00939

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.00842

AC:

12302

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00863

AC XY:

6274

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33480

American (AMR)

AF:

0.00597

AC:

267

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0362

AC:

947

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0119

AC:

1024

AN:

86258

European-Finnish (FIN)

AF:

0.00217

AC:

116

AN:

53420

Middle Eastern (MID)

AF:

0.0307

AC:

177

AN:

5768

European-Non Finnish (NFE)

AF:

0.00813

AC:

9041

AN:

1112010

Other (OTH)

AF:

0.0111

AC:

670

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

777

1554

2330

3107

3884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

338

676

1014

1352

1690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00693

AC:

1056

AN:

152272

Hom.:

Cov.:

AF XY:

0.00662

AC XY:

493

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41550

American (AMR)

AF:

0.00634

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00923

AC:

628

AN:

68018

Other (OTH)

AF:

0.0128

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

151

202

252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0112

Hom.:

Bravo

AF:

0.00686

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0113

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TGM2: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.094

(source)

DANN

Benign

0.49

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over