Genetic Variant TXNRD2:c.662+63T>C (chr22-19911314-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006440.5(TXNRD2):c.662+63T>C 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 1,310,984 control chromosomes in the GnomAD database, including 244,987 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 33451 hom., cov: 31)

Exomes 𝑓: 0.60 ( 211536 hom. )

Consequence

TXNRD2
NM_006440.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.58

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 22-19911314-A-G is Benign according to our data. Variant chr22-19911314-A-G is described in ClinVar as [Benign]. Clinvar id is 678039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5 link	c.662+63T>C		intron_variant	Intron 8 of 17	ENST00000400521.7	NP_006431.2	Q9NNW7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7 link	c.662+63T>C		intron_variant	Intron 8 of 17	1	NM_006440.5	ENSP00000383365.1		Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.654

AC:

99332

AN:

151876

Hom.:

33397

Cov.:

show subpopulations

Gnomad AFR

AF:

0.771

Gnomad AMI

AF:

0.531

Gnomad AMR

AF:

0.709

Gnomad ASJ

AF:

0.645

Gnomad EAS

AF:

0.922

Gnomad SAS

AF:

0.737

Gnomad FIN

AF:

0.618

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.553

Gnomad OTH

AF:

0.633

GnomAD4 exome

AF:

0.596

AC:

690983

AN:

1158990

Hom.:

211536

Cov.:

AF XY:

0.599

AC XY:

353590

AN XY:

590354

show subpopulations

Gnomad4 AFR exome

AF:

0.778

Gnomad4 AMR exome

AF:

0.774

Gnomad4 ASJ exome

AF:

0.645

Gnomad4 EAS exome

AF:

0.913

Gnomad4 SAS exome

AF:

0.712

Gnomad4 FIN exome

AF:

0.616

Gnomad4 NFE exome

AF:

0.552

Gnomad4 OTH exome

AF:

0.616

GnomAD4 genome

AF:

0.654

AC:

99448

AN:

151994

Hom.:

33451

Cov.:

AF XY:

0.661

AC XY:

49122

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.771

Gnomad4 AMR

AF:

0.710

Gnomad4 ASJ

AF:

0.645

Gnomad4 EAS

AF:

0.923

Gnomad4 SAS

AF:

0.738

Gnomad4 FIN

AF:

0.618

Gnomad4 NFE

AF:

0.553

Gnomad4 OTH

AF:

0.636

Alfa

AF:

0.594

Hom.:

5496

Bravo

AF:

0.667

Asia WGS

AF:

0.805

AC:

2799

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-0.92

CADD

Benign

0.12

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over