rs756661

chr22-19918279-G-Achr22-19918279-G-Cchr22-19918279-G-T

Variant summary

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

The NM_006440.5(TXNRD2):c.375-62C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.603 in 1,383,662 control chromosomes in the GnomAD database, including 257,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.65 (33372 hom., cov: 33)
  • Exomes 𝑓: 0.60 (224332 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.520

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=-0.94).
• BP6: Variant 22-19918279-G-A is Benign according to our data. Variant chr22-19918279-G-A is described in ClinVar as [Benign]. Clinvar id is 678090.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5	c.375-62C>T		intron_variant		ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7	c.375-62C>T		intron_variant		1	NM_006440.5	P4

Frequencies

GnomAD3 genomes AF: 0.652 AC: 99169 AN: 152046 Hom.: 33309 Cov.: 33

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.632

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.735

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.628

GnomAD4 exome AF: 0.597 AC: 735214 AN: 1231498 Hom.: 224332 AF XY: 0.599 AC XY: 373742 AN XY: 623594

Gnomad4 AFR exome AF: 0.780

Gnomad4 AMR exome AF: 0.772

Gnomad4 ASJ exome AF: 0.636

Gnomad4 EAS exome AF: 0.912

Gnomad4 SAS exome AF: 0.712

Gnomad4 FIN exome AF: 0.617

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.615

GnomAD4 genome AF: 0.653 AC: 99293 AN: 152164 Hom.: 33372 Cov.: 33 AF XY: 0.660 AC XY: 49071 AN XY: 74364

Gnomad4 AFR AF: 0.772

Gnomad4 AMR AF: 0.708

Gnomad4 ASJ AF: 0.632

Gnomad4 EAS AF: 0.924

Gnomad4 SAS AF: 0.736

Gnomad4 FIN AF: 0.618

Gnomad4 NFE AF: 0.550

Gnomad4 OTH AF: 0.631

Alfa AF: 0.579 Hom.: 53526

Bravo AF: 0.665

Asia WGS AF: 0.804 AC: 2792 AN: 3478

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 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	1.8
Dann	Benign	0.45

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: rs756661; hg19: chr22-19905802;