22-19933855-C-T

Variant names:

• chr22-19933855-C-T
• rs9605031
• NM_006440.5:c.104-2757G>A

Variant summary

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

The NM_006440.5(TXNRD2):​c.104-2757G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 152,178 control chromosomes in the GnomAD database, including 4,178 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 0.22 (4178 hom., cov: 32)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.153
• Publications: 16 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 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.104-2757G>A		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.104-2760G>A		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352302.2		c.-185-2757G>A		intron	N/A	NP_001339231.1	Q9NNW7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.104-2757G>A		intron	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.104-2760G>A		intron	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000542719.6	TSL:1	c.-185-2757G>A		intron	N/A	ENSP00000485128.2	Q9NNW7-3

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33867 AN: 152060 Hom.: 4176 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.249

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.223 AC: 33871 AN: 152178 Hom.: 4178 Cov.: 32 AF XY: 0.221 AC XY: 16467 AN XY: 74410

African (AFR) AF: 0.116 AC: 4824 AN: 41522

American (AMR) AF: 0.214 AC: 3273 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1423 AN: 5150

South Asian (SAS) AF: 0.264 AC: 1274 AN: 4830

European-Finnish (FIN) AF: 0.190 AC: 2013 AN: 10608

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18817 AN: 67988

Other (OTH) AF: 0.250 AC: 527 AN: 2110

Alfa AF: 0.258 Hom.: 4173

Bravo AF: 0.216

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.0
DANN	Benign	0.56
PhyloP100		-0.15
PromoterAI		0.0020	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: rs9605031; hg19: chr22-19921378;