rs202059967

Variant names:

• chr22-19878372-A-C
• rs202059967
• NM_006440.5:c.1341T>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19878372-A-C
• chr22-19878372-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PS3 BS2

The NM_006440.5(TXNRD2):​c.1341T>G​(p.Tyr447*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,613,726 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000883210: "Well-established functional studies show a deleterious effect". PMID:24601690". Synonymous variant affecting the same amino acid position (i.e. Y447Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: TXNRD2 NM_006440.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:2
• Conservation: PhyloP100: 1.80
• Publications: 6 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: Uncertain_significance. The variant received 0 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883210: "Well-established functional studies show a deleterious effect". PMID:24601690
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,Unknown,AR gene

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.1341T>G	p.Tyr447*	stop_gained	Exon 15 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.1338T>G	p.Tyr446*	stop_gained	Exon 15 of 17	NP_001339229.1
	TXNRD2	NM_001352301.2		c.1251T>G	p.Tyr417*	stop_gained	Exon 15 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.1341T>G	p.Tyr447*	stop_gained	Exon 15 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.1338T>G	p.Tyr446*	stop_gained	Exon 15 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.1251T>G	p.Tyr417*	stop_gained	Exon 15 of 18	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000565 AC: 141 AN: 249568 AF XY: 0.000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1461492 Hom.: 2 Cov.: 32 AF XY: 0.000384 AC XY: 279 AN XY: 727050

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00333 AC: 287 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53064

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1111974

Other (OTH) AF: 0.000331 AC: 20 AN: 60390

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74438

African (AFR) AF: 0.0000241 AC: 1 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.000694 AC: 84

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Glucocorticoid deficiency 5 (3)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	42
DANN	Uncertain	0.99
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.76	D
PhyloP100		1.8
Vest4		0.96
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs202059967; hg19: chr22-19865895;