22-19876812-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000400519.6(TXNRD2):c.*293C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 313,650 control chromosomes in the GnomAD database, including 2,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1156 hom., cov: 33)
  • Exomes 𝑓: 0.12 (1550 hom.)
• Consequence: TXNRD2 ENST00000400519.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.370

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-19876812-G-A is Benign according to our data. Variant chr22-19876812-G-A is described in ClinVar as [Benign]. Clinvar id is 1298115.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
TXNRD2	NM_006440.5	c.*65+228C>T		intron_variant		ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7	c.*65+228C>T		intron_variant		1	NM_006440.5	P4

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17011 AN: 152094 Hom.: 1152 Cov.: 33

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0921

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.124 AC: 20012 AN: 161438 Hom.: 1550 Cov.: 2 AF XY: 0.125 AC XY: 10260 AN XY: 81766

Gnomad4 AFR exome AF: 0.0508

Gnomad4 AMR exome AF: 0.0886

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.00579

Gnomad4 SAS exome AF: 0.0911

Gnomad4 FIN exome AF: 0.0898

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.112 AC: 17040 AN: 152212 Hom.: 1156 Cov.: 33 AF XY: 0.109 AC XY: 8137 AN XY: 74428

Gnomad4 AFR AF: 0.0554

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.0100

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0921

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.120

Alfa AF: 0.130 Hom.: 182

Bravo AF: 0.108

Asia WGS AF: 0.0670 AC: 232 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	3.0
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7287073; hg19: chr22-19864335; COSMIC: COSV68692950;