Genetic Variant NM_004613.4:c.1796A>T (chr20-38131210-T-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004613.4(TGM2):c.1796A>T(p.Gln599Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,461,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

TGM2
NM_004613.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17297062).

BS2

High AC in GnomAdExome4 at 52 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4 link	c.1796A>T	p.Gln599Leu	missense_variant	Exon 12 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.1796A>T	p.Gln599Leu	missense_variant	Exon 12 of 13	1	NM_004613.4	ENSP00000355330.2		P21980-1
TGM2	ENST00000469269.1 link	n.1441A>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000757

AC:

AN:

250948

AF XY:

0.0000959

show subpopulations

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:

0.0000356

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000481

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000568

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1796A>T (p.Q599L) alteration is located in exon 12 (coding exon 12) of the TGM2 gene. This alteration results from a A to T substitution at nucleotide position 1796, causing the glutamine (Q) at amino acid position 599 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

Eigen

Benign

0.037

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

M_CAP

Benign

0.053

MetaRNN

Benign

0.17

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.030

REVEL

Benign

0.17

Sift

Benign

0.25

Sift4G

Benign

0.41

Polyphen

0.057

Vest4

0.54

MutPred

0.58

Loss of disorder (P = 0.0402);

MVP

0.64

MPC

0.22

ClinPred

0.056

GERP RS

5.1

Varity_R

0.41

gMVP

0.67

Mutation Taster

=35/65

disease causing

(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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NM_004613.4:c.1796A>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over