ENST00000487165.5:n.1923A>G

Variant names:

• chr22-19875619-T-C
• rs1044732
• ENST00000487165.5:n.1923A>G

Variant summary

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

The ENST00000487165.5(TXNRD2):​n.1923A>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 0.119 in 145,368 control chromosomes in the GnomAD database, including 1,186 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 0.12 (1182 hom., cov: 34)
  • Exomes 𝑓: 0.14 (4 hom.)
• Consequence: TXNRD2 ENST00000487165.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.30
• Publications: 24 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=-0.59).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.*254A>G		3_prime_UTR_variant	Exon 18 of 18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.*254A>G		3_prime_UTR_variant	Exon 18 of 18	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17317 AN: 145112 Hom.: 1177 Cov.: 34

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.0922

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.138 AC: 22 AN: 160 Hom.: 4 Cov.: 0 AF XY: 0.148 AC XY: 19 AN XY: 128

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.138 AC: 19 AN: 138

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.119 AC: 17346 AN: 145208 Hom.: 1182 Cov.: 34 AF XY: 0.117 AC XY: 8278 AN XY: 71050

African (AFR) AF: 0.0747 AC: 2593 AN: 34722

American (AMR) AF: 0.108 AC: 1644 AN: 15164

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 696 AN: 3472

East Asian (EAS) AF: 0.0101 AC: 52 AN: 5170

South Asian (SAS) AF: 0.104 AC: 500 AN: 4796

European-Finnish (FIN) AF: 0.0922 AC: 978 AN: 10608

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.154 AC: 10441 AN: 67982

Other (OTH) AF: 0.122 AC: 256 AN: 2090

Alfa AF: 0.143 Hom.: 2116

Bravo AF: 0.110

Asia WGS AF: 0.0670 AC: 232 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1044732; hg19: chr22-19863142;