NM_006440.5:c.375-62C>T

Variant names:

• chr22-19918279-G-A
• rs756661
• NM_006440.5:c.375-62C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.520
• Publications: 16 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 -20 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 VariationId is 678090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.375-62C>T		intron_variant	Intron 4 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.375-62C>T		intron_variant	Intron 4 of 17	1	NM_006440.5	ENSP00000383365.1

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

African (AFR) AF: 0.780 AC: 22687 AN: 29086

American (AMR) AF: 0.772 AC: 33710 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 15682 AN: 24644

East Asian (EAS) AF: 0.912 AC: 35241 AN: 38642

South Asian (SAS) AF: 0.712 AC: 57862 AN: 81218

European-Finnish (FIN) AF: 0.617 AC: 31621 AN: 51244

Middle Eastern (MID) AF: 0.553 AC: 2950 AN: 5334

European-Non Finnish (NFE) AF: 0.556 AC: 502924 AN: 904740

Other (OTH) AF: 0.615 AC: 32537 AN: 52908

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

African (AFR) AF: 0.772 AC: 32038 AN: 41522

American (AMR) AF: 0.708 AC: 10831 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 2196 AN: 3472

East Asian (EAS) AF: 0.924 AC: 4775 AN: 5170

South Asian (SAS) AF: 0.736 AC: 3548 AN: 4822

European-Finnish (FIN) AF: 0.618 AC: 6538 AN: 10582

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37405 AN: 67992

Other (OTH) AF: 0.631 AC: 1333 AN: 2112

Alfa AF: 0.588 Hom.: 115295

Bravo AF: 0.665

Asia WGS AF: 0.804 AC: 2792 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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	-0.94
CADD	Benign	1.8
DANN	Benign	0.45
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs756661; hg19: chr22-19905802;