chr22-19933480-T-C

Variant names:

• chr22-19933480-T-C
• rs5746847
• ENST00000491939.6:c.-40A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352303.2(TXNRD2):​c.-40A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,289,174 control chromosomes in the GnomAD database, including 219,643 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28661 hom., cov: 32)
  • Exomes 𝑓: 0.58 (190982 hom.)
• Consequence: TXNRD2 NM_001352303.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.61
• Publications: 23 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)

LOC124905081 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352303.2. 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.104-2382A>G		intron	N/A	NP_006431.2
	TXNRD2	NM_001352303.2		c.-40A>G		5_prime_UTR	Exon 1 of 12	NP_001339232.1
	TXNRD2	NM_001352300.2		c.104-2385A>G		intron	N/A	NP_001339229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000491939.6	TSL:1	c.-40A>G		5_prime_UTR	Exon 1 of 12	ENSP00000485543.1
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.104-2382A>G		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.104-2385A>G		intron	N/A	ENSP00000383363.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92753 AN: 151924 Hom.: 28617 Cov.: 32

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.715

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.650

GnomAD2 exomes AF: 0.615 AC: 82722 AN: 134488 AF XY: 0.616

Gnomad AFR exome AF: 0.675

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.702

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.616

GnomAD4 exome AF: 0.578 AC: 656756 AN: 1137132 Hom.: 190982 Cov.: 45 AF XY: 0.580 AC XY: 323468 AN XY: 557888

African (AFR) AF: 0.682 AC: 16653 AN: 24406

American (AMR) AF: 0.644 AC: 18206 AN: 28256

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 11163 AN: 15938

East Asian (EAS) AF: 0.705 AC: 9054 AN: 12840

South Asian (SAS) AF: 0.635 AC: 48373 AN: 76186

European-Finnish (FIN) AF: 0.489 AC: 6392 AN: 13066

Middle Eastern (MID) AF: 0.606 AC: 2653 AN: 4378

European-Non Finnish (NFE) AF: 0.564 AC: 519121 AN: 920540

Other (OTH) AF: 0.605 AC: 25141 AN: 41522

GnomAD4 genome AF: 0.611 AC: 92853 AN: 152042 Hom.: 28661 Cov.: 32 AF XY: 0.611 AC XY: 45449 AN XY: 74330

African (AFR) AF: 0.680 AC: 28220 AN: 41502

American (AMR) AF: 0.666 AC: 10174 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.707 AC: 2453 AN: 3472

East Asian (EAS) AF: 0.714 AC: 3674 AN: 5148

South Asian (SAS) AF: 0.637 AC: 3070 AN: 4820

European-Finnish (FIN) AF: 0.480 AC: 5070 AN: 10566

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38193 AN: 67938

Other (OTH) AF: 0.651 AC: 1375 AN: 2112

Alfa AF: 0.590 Hom.: 100849

Bravo AF: 0.626

Asia WGS AF: 0.677 AC: 2355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0060
DANN	Benign	0.33
PhyloP100		-5.6
PromoterAI		0.0017	Neutral
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: rs5746847; hg19: chr22-19921003; COSMIC: COSV57632551; COSMIC: COSV57632551;