22-19895453-G-T

Variant names:

• chr22-19895453-G-T
• rs35695986
• NM_006440.5:c.903C>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006440.5(TXNRD2):​c.903C>A​(p.Thr301Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,613,934 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (26 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (33 hom.)
• Consequence: TXNRD2 NM_006440.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.54

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-19895453-G-T is Benign according to our data. Variant chr22-19895453-G-T is described in ClinVar as [Benign]. Clinvar id is 240657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19895453-G-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.54 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1684/152330) while in subpopulation AFR AF= 0.0379 (1577/41582). AF 95% confidence interval is 0.0364. There are 26 homozygotes in gnomad4. There are 773 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.903C>A	p.Thr301Thr	synonymous_variant	Exon 11 of 18	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.903C>A	p.Thr301Thr	synonymous_variant	Exon 11 of 18	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1684 AN: 152212 Hom.: 26 Cov.: 33

Gnomad AFR AF: 0.0380

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00286 AC: 712 AN: 249044 Hom.: 14 AF XY: 0.00210 AC XY: 284 AN XY: 135128

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000452

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00145 AC: 2123 AN: 1461604 Hom.: 33 Cov.: 33 AF XY: 0.00130 AC XY: 947 AN XY: 727090

Gnomad4 AFR exome AF: 0.0415

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000348

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.0111 AC: 1684 AN: 152330 Hom.: 26 Cov.: 33 AF XY: 0.0104 AC XY: 773 AN XY: 74492

Gnomad4 AFR AF: 0.0379

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.000912 Hom.: 1

Bravo AF: 0.0130

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Aug 14, 2017

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Primary dilated cardiomyopathy Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Aug 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

TXNRD2-related disorder Benign:1

Jul 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.051
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35695986; hg19: chr22-19882976;