NM_006440.5:c.592-869C>T

Variant names:

• chr22-19912316-G-A
• rs7410379
• NM_006440.5:c.592-869C>T

Variant summary

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

The NM_006440.5(TXNRD2):​c.592-869C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 152,188 control chromosomes in the GnomAD database, including 7,287 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 0.30 (7287 hom., cov: 34)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.528
• Publications: 12 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.592-869C>T		intron_variant	Intron 7 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.592-869C>T		intron_variant	Intron 7 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44912 AN: 152070 Hom.: 7285 Cov.: 34

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.295 AC: 44928 AN: 152188 Hom.: 7287 Cov.: 34 AF XY: 0.302 AC XY: 22435 AN XY: 74400

African (AFR) AF: 0.204 AC: 8476 AN: 41542

American (AMR) AF: 0.379 AC: 5795 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3468

East Asian (EAS) AF: 0.646 AC: 3332 AN: 5160

South Asian (SAS) AF: 0.383 AC: 1846 AN: 4826

European-Finnish (FIN) AF: 0.318 AC: 3366 AN: 10598

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.290 AC: 19713 AN: 67974

Other (OTH) AF: 0.302 AC: 637 AN: 2112

Alfa AF: 0.290 Hom.: 5569

Bravo AF: 0.299

Asia WGS AF: 0.455 AC: 1582 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.4
DANN	Benign	0.81
PhyloP100		0.53
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: rs7410379; hg19: chr22-19899839;