22-19933480-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000491939.6(TXNRD2):c.-40A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,289,174 control chromosomes in the GnomAD database, including 219,643 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28661 hom., cov: 32)
  • Exomes 𝑓: 0.58 (190982 hom.)
• Consequence: TXNRD2 ENST00000491939.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.61

Genes affected

TXNRD2 (HGNC:18155): (thioredoxin reductase 2) The protein encoded by this gene belongs to the pyridine nucleotide-disulfide oxidoreductase family, and is a member of the thioredoxin (Trx) system. Three thioredoxin reductase (TrxR) isozymes are found in mammals. TrxRs are selenocysteine-containing flavoenzymes, which reduce thioredoxins, as well as other substrates, and play a key role in redox homoeostasis. This gene encodes a mitochondrial form important for scavenging reactive oxygen species in mitochondria. It functions as a homodimer containing FAD, and selenocysteine (Sec) at the active site. Sec is encoded by UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, the Sec insertion sequence (SECIS) element, which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Alternatively spliced transcript variants encoding different isoforms, including a few localized in the cytosol and some lacking the C-terminal Sec residue, have been found for this gene. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5	c.104-2382A>G		intron_variant		ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7	c.104-2382A>G		intron_variant		1	NM_006440.5	P4

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92753 AN: 151924 Hom.: 28617 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.650

GnomAD3 exomes AF: 0.615 AC: 82722 AN: 134488 Hom.: 25769 AF XY: 0.616 AC XY: 45104 AN XY: 73252

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.702

Gnomad SAS exome AF: 0.646

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.578 AC: 656756 AN: 1137132 Hom.: 190982 Cov.: 45 AF XY: 0.580 AC XY: 323468 AN XY: 557888

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.644

Gnomad4 ASJ exome AF: 0.700

Gnomad4 EAS exome AF: 0.705

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.489

Gnomad4 NFE exome AF: 0.564

Gnomad4 OTH exome AF: 0.605

GnomAD4 genome AF: 0.611 AC: 92853 AN: 152042 Hom.: 28661 Cov.: 32 AF XY: 0.611 AC XY: 45449 AN XY: 74330

Gnomad4 AFR AF: 0.680

Gnomad4 AMR AF: 0.666

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.714

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.651

Alfa AF: 0.590 Hom.: 50692

Bravo AF: 0.626

Asia WGS AF: 0.677 AC: 2355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.0060
Dann	Benign	0.33

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

LitVar

Other links and lift over

dbSNP: rs5746847; hg19: chr22-19921003; COSMIC: COSV57632551; COSMIC: COSV57632551;