22-19933123-C-G

Variant names:

• chr22-19933123-C-G
• rs5746846
• NM_006440.5:c.104-2025G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000400521.7(TXNRD2):​c.104-2025G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 152,126 control chromosomes in the GnomAD database, including 20,989 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 0.52 (20989 hom., cov: 33)
• Consequence: TXNRD2 ENST00000400521.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 13 publications found

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]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000400521.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	NM_006440.5	MANE Select	c.104-2025G>C		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.104-2028G>C		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352302.2		c.-185-2025G>C		intron	N/A	NP_001339231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.104-2025G>C		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.104-2028G>C		intron	N/A	ENSP00000383363.1
	TXNRD2	ENST00000542719.6	TSL:1	c.-185-2025G>C		intron	N/A	ENSP00000485128.2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79432 AN: 152006 Hom.: 20972 Cov.: 33

Gnomad AFR AF: 0.480

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.459

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.552

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.523 AC: 79494 AN: 152126 Hom.: 20989 Cov.: 33 AF XY: 0.526 AC XY: 39083 AN XY: 74370

African (AFR) AF: 0.480 AC: 19940 AN: 41502

American (AMR) AF: 0.592 AC: 9055 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2351 AN: 3468

East Asian (EAS) AF: 0.693 AC: 3576 AN: 5160

South Asian (SAS) AF: 0.533 AC: 2570 AN: 4824

European-Finnish (FIN) AF: 0.459 AC: 4859 AN: 10590

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.521 AC: 35391 AN: 67982

Other (OTH) AF: 0.554 AC: 1170 AN: 2112

Alfa AF: 0.520 Hom.: 2557

Bravo AF: 0.531

Asia WGS AF: 0.602 AC: 2096 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.43
PhyloP100		-2.4
PromoterAI		0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs5746846; hg19: chr22-19920646;