chr20-38130360-G-A

Variant names:

• chr20-38130360-G-A
• rs2229472
• NM_004613.4:c.1923C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004613.4(TGM2):​c.1923C>T​(p.Pro641Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,592,258 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (28 hom.)
• Consequence: TGM2 NM_004613.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.10
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 20-38130360-G-A is Benign according to our data. Variant chr20-38130360-G-A is described in ClinVar as [Benign]. Clinvar id is 786676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1677/152282) while in subpopulation AFR AF = 0.0379 (1576/41562). AF 95% confidence interval is 0.0364. There are 27 homozygotes in GnomAd4. There are 793 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1677 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGM2	NM_004613.4	c.1923C>T	p.Pro641Pro	synonymous_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.1923C>T	p.Pro641Pro	synonymous_variant	Exon 13 of 13	1	NM_004613.4	ENSP00000355330.2
TGM2	ENST00000469269.1	n.1568C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1677 AN: 152164 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00278 AC: 578 AN: 208242 AF XY: 0.00208

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000271

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00121 AC: 1741 AN: 1439976 Hom.: 28 Cov.: 30 AF XY: 0.00104 AC XY: 740 AN XY: 713800

African (AFR) AF: 0.0378 AC: 1259 AN: 33316

American (AMR) AF: 0.00221 AC: 89 AN: 40288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38952

South Asian (SAS) AF: 0.0000606 AC: 5 AN: 82484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52044

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5726

European-Non Finnish (NFE) AF: 0.000201 AC: 222 AN: 1101920

Other (OTH) AF: 0.00256 AC: 153 AN: 59704

GnomAD4 genome AF: 0.0110 AC: 1677 AN: 152282 Hom.: 27 Cov.: 32 AF XY: 0.0107 AC XY: 793 AN XY: 74452

African (AFR) AF: 0.0379 AC: 1576 AN: 41562

American (AMR) AF: 0.00431 AC: 66 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68018

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00499 Hom.: 12

Bravo AF: 0.0123

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.59
DANN	Benign	0.43
PhyloP100		-2.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2229472; hg19: chr20-36758762;