rs186462665

Variant names:

• chr22-19919562-G-A
• rs186462665
• ENST00000542719.6:c.-79C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001352302.2(TXNRD2):​c.-79C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,563,300 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (8 hom., cov: 27)
  • Exomes 𝑓: 0.0013 (27 hom.)
• Consequence: TXNRD2 NM_001352302.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.283
• Publications: 3 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 22-19919562-G-A is Benign according to our data. Variant chr22-19919562-G-A is described in ClinVar as Benign. ClinVar VariationId is 454283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AD,Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352302.2. 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.210C>T	p.Tyr70Tyr	synonymous	Exon 3 of 18	NP_006431.2
	TXNRD2	NM_001352302.2		c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	NP_001339231.1	Q9NNW7-3
	TXNRD2	NM_001352300.2		c.207C>T	p.Tyr69Tyr	synonymous	Exon 3 of 17	NP_001339229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000542719.6	TSL:1	c.-79C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000485128.2	Q9NNW7-3
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.210C>T	p.Tyr70Tyr	synonymous	Exon 3 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.207C>T	p.Tyr69Tyr	synonymous	Exon 3 of 17	ENSP00000383363.1	A0A182DWF3

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 478 AN: 151966 Hom.: 8 Cov.: 27

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0391

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00338 AC: 587 AN: 173480 AF XY: 0.00295

Gnomad AFR exome AF: 0.000102

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000173

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.000356

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.00133 AC: 1875 AN: 1411216 Hom.: 27 Cov.: 30 AF XY: 0.00124 AC XY: 866 AN XY: 697532

African (AFR) AF: 0.0000312 AC: 1 AN: 32080

American (AMR) AF: 0.00 AC: 0 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25266

East Asian (EAS) AF: 0.0000832 AC: 3 AN: 36062

South Asian (SAS) AF: 0.00 AC: 0 AN: 79826

European-Finnish (FIN) AF: 0.0314 AC: 1572 AN: 50100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.000213 AC: 232 AN: 1086658

Other (OTH) AF: 0.00114 AC: 67 AN: 58556

GnomAD4 genome AF: 0.00314 AC: 478 AN: 152084 Hom.: 8 Cov.: 27 AF XY: 0.00466 AC XY: 346 AN XY: 74326

African (AFR) AF: 0.000241 AC: 10 AN: 41520

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0391 AC: 414 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000856 Hom.: 0

Bravo AF: 0.000238

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.2
DANN	Benign	0.86
PhyloP100		-0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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: rs186462665; hg19: chr22-19907085;