22-19875633-TGG-TGGG

Variant names:

• chr22-19875633-T-TG
• rs59339361
• ENST00000487165.5:n.1908dupC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_006440.5(TXNRD2):​c.*239dupC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 151,090 control chromosomes in the GnomAD database, including 20 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (20 hom., cov: 23)
  • Exomes 𝑓: 0.012 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 22-19875633-T-TG is Benign according to our data. Variant chr22-19875633-T-TG is described in ClinVar as [Likely_benign]. Clinvar id is 1320491.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0112 (1694/150926) while in subpopulation AMR AF = 0.0388 (588/15174). AF 95% confidence interval is 0.0362. There are 20 homozygotes in GnomAd4. There are 898 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.*239dupC		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.*239dupC		3_prime_UTR_variant	Exon 18 of 18	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1692 AN: 150808 Hom.: 20 Cov.: 23

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.0496

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.00797

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.0232

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00868

Gnomad OTH AF: 0.00680

GnomAD4 exome AF: 0.0122 AC: 2 AN: 164 Hom.: 0 Cov.: 0 AF XY: 0.00781 AC XY: 1 AN XY: 128

African (AFR) AF: 0.00 AC: 0 AN: 10

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0149 AC: 2 AN: 134

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.0112 AC: 1694 AN: 150926 Hom.: 20 Cov.: 23 AF XY: 0.0122 AC XY: 898 AN XY: 73678

African (AFR) AF: 0.00373 AC: 154 AN: 41310

American (AMR) AF: 0.0388 AC: 588 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.00377 AC: 13 AN: 3446

East Asian (EAS) AF: 0.00799 AC: 41 AN: 5134

South Asian (SAS) AF: 0.00232 AC: 11 AN: 4738

European-Finnish (FIN) AF: 0.0232 AC: 240 AN: 10354

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00868 AC: 586 AN: 67488

Other (OTH) AF: 0.00672 AC: 14 AN: 2082

Alfa AF: 0.0116 Hom.: 38

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

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: rs59339361; hg19: chr22-19863156;