rs12158214

Variant names:

• chr22-19884168-C-T
• rs12158214
• ENST00000487165.5:n.337G>A

Variant summary

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

The ENST00000487165.5(TXNRD2):​n.337G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 152,502 control chromosomes in the GnomAD database, including 3,656 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 0.20 (3648 hom., cov: 32)
  • Exomes 𝑓: 0.15 (8 hom.)
• Consequence: TXNRD2 ENST00000487165.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125
• Publications: 9 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 (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.950-707G>A		intron_variant	Intron 11 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.950-707G>A		intron_variant	Intron 11 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29888 AN: 151876 Hom.: 3633 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.199

Gnomad EAS AF: 0.00986

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0914

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.146 AC: 74 AN: 508 Hom.: 8 Cov.: 0 AF XY: 0.151 AC XY: 53 AN XY: 352

African (AFR) AF: 0.500 AC: 3 AN: 6

American (AMR) AF: 0.300 AC: 3 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 20

South Asian (SAS) AF: 0.125 AC: 4 AN: 32

European-Finnish (FIN) AF: 0.0500 AC: 1 AN: 20

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.153 AC: 58 AN: 380

Other (OTH) AF: 0.0938 AC: 3 AN: 32

GnomAD4 genome AF: 0.197 AC: 29946 AN: 151994 Hom.: 3648 Cov.: 32 AF XY: 0.191 AC XY: 14168 AN XY: 74312

African (AFR) AF: 0.338 AC: 14009 AN: 41404

American (AMR) AF: 0.143 AC: 2180 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 690 AN: 3468

East Asian (EAS) AF: 0.00988 AC: 51 AN: 5162

South Asian (SAS) AF: 0.104 AC: 503 AN: 4816

European-Finnish (FIN) AF: 0.0914 AC: 968 AN: 10586

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10959 AN: 67970

Other (OTH) AF: 0.181 AC: 383 AN: 2112

Alfa AF: 0.182 Hom.: 437

Bravo AF: 0.205

Asia WGS AF: 0.0810 AC: 281 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.63
PhyloP100		-0.13
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: rs12158214; hg19: chr22-19871691;