chr22-19894033-A-G

Variant names:

• chr22-19894033-A-G
• rs5992493
• ENST00000491939.6:c.*1100T>C

Variant summary

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

The NM_001282512.3(TXNRD2):​c.*1100T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 152,196 control chromosomes in the GnomAD database, including 7,699 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 0.27 (7699 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: TXNRD2 NM_001282512.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.314
• Publications: 14 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282512.3. 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.949+1374T>C		intron	N/A	NP_006431.2
	TXNRD2	NM_001282512.3		c.*1100T>C		3_prime_UTR	Exon 12 of 12	NP_001269441.1
	TXNRD2	NM_001352303.2		c.*1100T>C		3_prime_UTR	Exon 12 of 12	NP_001339232.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000491939.6	TSL:1	c.*1100T>C		3_prime_UTR	Exon 12 of 12	ENSP00000485543.1
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.949+1374T>C		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.946+1374T>C		intron	N/A	ENSP00000383363.1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40559 AN: 152062 Hom.: 7664 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0558

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.250 AC: 4 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.200 AC XY: 2 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.333 AC: 2 AN: 6

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.267 AC: 40666 AN: 152180 Hom.: 7699 Cov.: 33 AF XY: 0.261 AC XY: 19419 AN XY: 74404

African (AFR) AF: 0.535 AC: 22184 AN: 41474

American (AMR) AF: 0.200 AC: 3056 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 616 AN: 3472

East Asian (EAS) AF: 0.0559 AC: 290 AN: 5184

South Asian (SAS) AF: 0.207 AC: 998 AN: 4830

European-Finnish (FIN) AF: 0.125 AC: 1331 AN: 10606

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11568 AN: 68000

Other (OTH) AF: 0.244 AC: 515 AN: 2110

Alfa AF: 0.209 Hom.: 2510

Bravo AF: 0.284

Asia WGS AF: 0.161 AC: 558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.6
DANN	Benign	0.53
PhyloP100		0.31
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: rs5992493; hg19: chr22-19881556;