22-19912552-A-G

Variant names:

• chr22-19912552-A-G
• rs1005873
• NM_006440.5:c.592-1105T>C

Variant summary

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

The NM_006440.5(TXNRD2):​c.592-1105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 152,080 control chromosomes in the GnomAD database, including 6,041 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 0.24 (6041 hom., cov: 33)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149
• Publications: 10 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006440.5. 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.592-1105T>C		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.589-1105T>C		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.502-1105T>C		intron	N/A	NP_001339230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.592-1105T>C		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.589-1105T>C		intron	N/A	ENSP00000383363.1
	TXNRD2	ENST00000400518.5	TSL:1	c.502-1105T>C		intron	N/A	ENSP00000383362.1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 36010 AN: 151962 Hom.: 6016 Cov.: 33

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.209

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

GnomAD4 genome AF: 0.237 AC: 36095 AN: 152080 Hom.: 6041 Cov.: 33 AF XY: 0.241 AC XY: 17899 AN XY: 74348

African (AFR) AF: 0.470 AC: 19475 AN: 41474

American (AMR) AF: 0.221 AC: 3386 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3468

East Asian (EAS) AF: 0.267 AC: 1382 AN: 5174

South Asian (SAS) AF: 0.249 AC: 1201 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1893 AN: 10584

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7809 AN: 67954

Other (OTH) AF: 0.212 AC: 448 AN: 2110

Alfa AF: 0.139 Hom.: 2459

Bravo AF: 0.249

Asia WGS AF: 0.275 AC: 952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.53
PhyloP100		0.15
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: rs1005873; hg19: chr22-19900075;