rs924234485

Variant names:

• chr20-38130368-G-A
• rs924234485
• NM_004613.4:c.1915C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004613.4(TGM2):​c.1915C>T​(p.Pro639Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGM2 NM_004613.4 missense, splice_region
• Scores: Splicing: ADA: 0.00001439
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07220858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4	c.1915C>T	p.Pro639Ser	missense_variant, splice_region_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.1915C>T	p.Pro639Ser	missense_variant, splice_region_variant	Exon 13 of 13	1	NM_004613.4	ENSP00000355330.2
TGM2	ENST00000469269.1	n.1560C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1915C>T (p.P639S) alteration is located in exon 13 (coding exon 13) of the TGM2 gene. This alteration results from a C to T substitution at nucleotide position 1915, causing the proline (P) at amino acid position 639 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.3
DANN	Benign	0.24
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.71
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.065
Sift	Benign	0.73	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.027
MutPred		0.46		Gain of phosphorylation at P639 (P = 0.0584);
MVP		0.39
MPC		0.23
ClinPred		0.020	T
GERP RS		0.80
Varity_R		0.10
gMVP		0.42
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs924234485; hg19: chr20-36758770;