Genetic Variant TGM2:p.Val542Phe (chr20-38132492-C-A) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004613.4(TGM2):c.1624G>T(p.Val542Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,614,104 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0054 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 14 hom. )

Consequence

TGM2
NM_004613.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.14

Publications

10 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009551823).

BP6

Variant 20-38132492-C-A is Benign according to our data. Variant chr20-38132492-C-A is described in ClinVar as [Benign]. Clinvar id is 713744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 824 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4 link	c.1624G>T	p.Val542Phe	missense_variant	Exon 11 of 13	ENST00000361475.7	NP_004604.2	P21980-1V9HWG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM2	ENST00000361475.7 link	c.1624G>T	p.Val542Phe	missense_variant	Exon 11 of 13	1	NM_004613.4	ENSP00000355330.2		P21980-1
TGM2	ENST00000469269.1 link	n.1269G>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00538

AC:

819

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0112

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0149

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00368

AC:

925

AN:

251470

AF XY:

0.00335

show subpopulations

Gnomad AFR exome

AF:

0.0108

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0162

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00200

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00236

AC:

3444

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1741

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00965

AC:

323

AN:

33480

American (AMR)

AF:

0.00206

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

26136

East Asian (EAS)

AF:

0.0127

AC:

506

AN:

39700

South Asian (SAS)

AF:

0.00283

AC:

244

AN:

86254

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00178

AC:

1977

AN:

1111996

Other (OTH)

AF:

0.00267

AC:

161

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

209

417

626

834

1043

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00541

AC:

824

AN:

152254

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0113

AC:

471

AN:

41546

American (AMR)

AF:

0.00451

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.0145

AC:

AN:

5170

South Asian (SAS)

AF:

0.00373

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00219

AC:

149

AN:

68010

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

138

184

230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00332

Hom.:

Bravo

AF:

0.00558

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00389

AC:

472

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00249

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.11

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0096

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.81

REVEL

Benign

0.28

Sift

Benign

0.56

Sift4G

Benign

0.69

Polyphen

0.98

Vest4

0.47

MVP

0.70

MPC

0.91

ClinPred

0.015

GERP RS

-0.24

Varity_R

0.61

gMVP

0.85

Mutation Taster

=85/15

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.

20-38132492-C-A

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