22-19939623-A-C

Variant names:

• chr22-19939623-A-C
• rs5748489
• NM_006440.5:c.103+2078T>G

Variant summary

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

The NM_006440.5(TXNRD2):​c.103+2078T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 151,996 control chromosomes in the GnomAD database, including 29,977 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 0.62 (29977 hom., cov: 31)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 7 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)

ENSG00000289946 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.103+2078T>G		intron_variant	Intron 1 of 17	ENST00000400521.7	NP_006431.2
TXNRD2	NM_001352300.2	c.103+2078T>G		intron_variant	Intron 1 of 16		NP_001339229.1
TXNRD2	NM_001282512.3	c.103+2078T>G		intron_variant	Intron 1 of 11		NP_001269441.1
TXNRD2	NR_147957.2	n.118+2078T>G		intron_variant	Intron 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+2078T>G		intron_variant	Intron 1 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94578 AN: 151878 Hom.: 29924 Cov.: 31

Gnomad AFR AF: 0.723

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.663

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

GnomAD4 genome AF: 0.623 AC: 94691 AN: 151996 Hom.: 29977 Cov.: 31 AF XY: 0.623 AC XY: 46308 AN XY: 74276

African (AFR) AF: 0.723 AC: 29963 AN: 41432

American (AMR) AF: 0.669 AC: 10223 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 2451 AN: 3470

East Asian (EAS) AF: 0.714 AC: 3680 AN: 5156

South Asian (SAS) AF: 0.637 AC: 3070 AN: 4822

European-Finnish (FIN) AF: 0.480 AC: 5071 AN: 10560

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.562 AC: 38204 AN: 67958

Other (OTH) AF: 0.664 AC: 1404 AN: 2114

Alfa AF: 0.600 Hom.: 4317

Bravo AF: 0.640

Asia WGS AF: 0.679 AC: 2362 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.32
PhyloP100		-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: rs5748489; hg19: chr22-19927146;