22-19905557-A-G

Variant names:

• chr22-19905557-A-G
• rs9606174
• NM_006440.5:c.662+5820T>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.662+5820T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,052 control chromosomes in the GnomAD database, including 4,054 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 0.21 (4054 hom., cov: 31)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.720
• Publications: 6 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 = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.662+5820T>C		intron_variant	Intron 8 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.662+5820T>C		intron_variant	Intron 8 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31132 AN: 151932 Hom.: 4030 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.207

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.205 AC: 31214 AN: 152052 Hom.: 4054 Cov.: 31 AF XY: 0.210 AC XY: 15581 AN XY: 74320

African (AFR) AF: 0.360 AC: 14930 AN: 41432

American (AMR) AF: 0.208 AC: 3179 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1359 AN: 5150

South Asian (SAS) AF: 0.247 AC: 1192 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1893 AN: 10586

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

European-Non Finnish (NFE) AF: 0.114 AC: 7768 AN: 67984

Other (OTH) AF: 0.186 AC: 392 AN: 2110

Alfa AF: 0.170 Hom.: 353

Bravo AF: 0.213

Asia WGS AF: 0.267 AC: 927 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.61
DANN	Benign	0.36
PhyloP100		-0.72
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: rs9606174; hg19: chr22-19893080;