rs1139793

Variant names:

• chr22-19880695-A-G
• rs1139793
• NM_006440.5:c.1109T>C

Your query was ambiguous. Multiple possible variants found:

• chr22-19880695-A-G
• chr22-19880695-A-C

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.1109T>C​(p.Ile370Thr) variant causes a missense change. The variant allele was found at a frequency of 0.723 in 1,612,762 control chromosomes in the GnomAD database, including 426,057 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.77 (45518 hom., cov: 33)
  • Exomes 𝑓: 0.72 (380539 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.83
• Publications: 62 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 (MetaRNN=2.917005E-6).
• BP6: Variant 22-19880695-A-G is Benign according to our data. Variant chr22-19880695-A-G is described in ClinVar as Benign. ClinVar VariationId is 263369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006440.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	NM_006440.5	MANE Select	c.1109T>C	p.Ile370Thr	missense	Exon 13 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.1106T>C	p.Ile369Thr	missense	Exon 13 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.1019T>C	p.Ile340Thr	missense	Exon 13 of 18	NP_001339230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.1109T>C	p.Ile370Thr	missense	Exon 13 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.1106T>C	p.Ile369Thr	missense	Exon 13 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.1019T>C	p.Ile340Thr	missense	Exon 13 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116456 AN: 152004 Hom.: 45452 Cov.: 33

Gnomad AFR AF: 0.917

Gnomad AMI AF: 0.892

Gnomad AMR AF: 0.658

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.603

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.777

GnomAD2 exomes AF: 0.691 AC: 171567 AN: 248132 AF XY: 0.689

Gnomad AFR exome AF: 0.920

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.767

Gnomad EAS exome AF: 0.592

Gnomad FIN exome AF: 0.685

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.706

GnomAD4 exome AF: 0.719 AC: 1049835 AN: 1460640 Hom.: 380539 Cov.: 54 AF XY: 0.716 AC XY: 520024 AN XY: 726630

African (AFR) AF: 0.926 AC: 31012 AN: 33476

American (AMR) AF: 0.578 AC: 25854 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 20107 AN: 26134

East Asian (EAS) AF: 0.630 AC: 25023 AN: 39700

South Asian (SAS) AF: 0.586 AC: 50558 AN: 86244

European-Finnish (FIN) AF: 0.688 AC: 36087 AN: 52446

Middle Eastern (MID) AF: 0.784 AC: 4519 AN: 5764

European-Non Finnish (NFE) AF: 0.731 AC: 813035 AN: 1111798

Other (OTH) AF: 0.723 AC: 43640 AN: 60376

GnomAD4 genome AF: 0.766 AC: 116583 AN: 152122 Hom.: 45518 Cov.: 33 AF XY: 0.758 AC XY: 56369 AN XY: 74358

African (AFR) AF: 0.917 AC: 38097 AN: 41556

American (AMR) AF: 0.658 AC: 10057 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3470

East Asian (EAS) AF: 0.602 AC: 3098 AN: 5142

South Asian (SAS) AF: 0.582 AC: 2803 AN: 4820

European-Finnish (FIN) AF: 0.685 AC: 7244 AN: 10582

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49899 AN: 67966

Other (OTH) AF: 0.777 AC: 1635 AN: 2104

Alfa AF: 0.746 Hom.: 132245

Bravo AF: 0.773

TwinsUK AF: 0.726 AC: 2691

ALSPAC AF: 0.722 AC: 2781

ESP6500AA AF: 0.916 AC: 3747

ESP6500EA AF: 0.738 AC: 6182

ExAC AF: 0.700 AC: 84557

Asia WGS AF: 0.617 AC: 2148 AN: 3478

EpiCase AF: 0.749

EpiControl AF: 0.750

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Glucocorticoid deficiency 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0000029	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.59	N
PhyloP100		5.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.26
ClinPred		0.028	T
GERP RS		5.4
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1139793; hg19: chr22-19868218; COSMIC: COSV68691528;