22-19875633-T-TG

Position:

• chr22-19875633-T-TG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_006440.5(TXNRD2):​c.*239_*240insC 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

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.*239_*240insC		3_prime_UTR_variant	18/18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.*239_*240insC		3_prime_UTR_variant	18/18	1	NM_006440.5	ENSP00000383365	P4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.0388

Gnomad4 ASJ AF: 0.00377

Gnomad4 EAS AF: 0.00799

Gnomad4 SAS AF: 0.00232

Gnomad4 FIN AF: 0.0232

Gnomad4 NFE AF: 0.00868

Gnomad4 OTH AF: 0.00672

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs59339361; hg19: chr22-19863156;