chr22-19920696-C-T

Variant names:

• chr22-19920696-C-T
• rs1978058
• NM_006440.5:c.173-1097G>A

Variant summary

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

The NM_006440.5(TXNRD2):​c.173-1097G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 152,172 control chromosomes in the GnomAD database, including 9,112 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 0.34 (9112 hom., cov: 33)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 11 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 (NFE) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.173-1097G>A		intron_variant	Intron 2 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.173-1097G>A		intron_variant	Intron 2 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51432 AN: 152058 Hom.: 9108 Cov.: 33

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.0650

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.339

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

GnomAD4 genome AF: 0.338 AC: 51475 AN: 152172 Hom.: 9112 Cov.: 33 AF XY: 0.330 AC XY: 24509 AN XY: 74382

African (AFR) AF: 0.335 AC: 13895 AN: 41528

American (AMR) AF: 0.282 AC: 4315 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1176 AN: 3472

East Asian (EAS) AF: 0.0651 AC: 337 AN: 5176

South Asian (SAS) AF: 0.341 AC: 1644 AN: 4826

European-Finnish (FIN) AF: 0.296 AC: 3131 AN: 10564

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.380 AC: 25856 AN: 68006

Other (OTH) AF: 0.339 AC: 715 AN: 2110

Alfa AF: 0.366 Hom.: 19170

Bravo AF: 0.333

Asia WGS AF: 0.205 AC: 717 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.47
PhyloP100		1.2
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: rs1978058; hg19: chr22-19908219;