rs3788306

Variant names:

• chr22-19884486-T-C
• rs3788306
• ENST00000487165.5:n.19A>G

Variant summary

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

The ENST00000487165.5(TXNRD2):​n.19A>G 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 0.253 in 152,220 control chromosomes in the GnomAD database, including 5,153 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 0.25 (5140 hom., cov: 32)
  • Exomes 𝑓: 0.37 (13 hom.)
• Consequence: TXNRD2 ENST00000487165.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.591
• Publications: 18 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.950-1025A>G		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.950-1025A>G		intron_variant	Intron 11 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38373 AN: 151924 Hom.: 5134 Cov.: 32

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.365 AC: 65 AN: 178 Hom.: 13 Cov.: 0 AF XY: 0.352 AC XY: 50 AN XY: 142

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 2 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 4 AN: 8

Middle Eastern (MID) AF: 0.250 AC: 1 AN: 4

European-Non Finnish (NFE) AF: 0.368 AC: 53 AN: 144

Other (OTH) AF: 0.333 AC: 4 AN: 12

GnomAD4 genome AF: 0.252 AC: 38388 AN: 152042 Hom.: 5140 Cov.: 32 AF XY: 0.252 AC XY: 18699 AN XY: 74318

African (AFR) AF: 0.163 AC: 6765 AN: 41522

American (AMR) AF: 0.258 AC: 3940 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1420 AN: 5134

South Asian (SAS) AF: 0.219 AC: 1056 AN: 4822

European-Finnish (FIN) AF: 0.274 AC: 2893 AN: 10570

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20102 AN: 67928

Other (OTH) AF: 0.263 AC: 555 AN: 2112

Alfa AF: 0.285 Hom.: 17300

Bravo AF: 0.250

Asia WGS AF: 0.216 AC: 750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.5
DANN	Benign	0.71
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3788306; hg19: chr22-19872009;