20-38130356-C-T

Variant names:

• chr20-38130356-C-T
• rs1195870646
• NM_004613.4:c.1927G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004613.4(TGM2):​c.1927G>A​(p.Glu643Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000502 in 1,594,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: TGM2 NM_004613.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.82
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24293002).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4	c.1927G>A	p.Glu643Lys	missense_variant	Exon 13 of 13	ENST00000361475.7	NP_004604.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGM2	ENST00000361475.7	c.1927G>A	p.Glu643Lys	missense_variant	Exon 13 of 13	1	NM_004613.4	ENSP00000355330.2
TGM2	ENST00000469269.1	n.1572G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1442170 Hom.: 0 Cov.: 30 AF XY: 0.00000420 AC XY: 3 AN XY: 715122

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 40708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25572

East Asian (EAS) AF: 0.00 AC: 0 AN: 39066

South Asian (SAS) AF: 0.00 AC: 0 AN: 82692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000635 AC: 7 AN: 1103106

Other (OTH) AF: 0.00 AC: 0 AN: 59794

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1927G>A (p.E643K) alteration is located in exon 13 (coding exon 13) of the TGM2 gene. This alteration results from a G to A substitution at nucleotide position 1927, causing the glutamic acid (E) at amino acid position 643 to be replaced by a lysine (K). 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	0.065
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.77
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.16
Sift	Benign	0.81	T
Sift4G	Benign	0.74	T
Polyphen		0.50	P
Vest4		0.20
MutPred		0.48		Gain of ubiquitination at E643 (P = 0.0203);
MVP		0.64
MPC		0.28
ClinPred		0.28	T
GERP RS		3.2
Varity_R		0.11
gMVP		0.60
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1195870646; hg19: chr20-36758758;