22-19933614-C-T

Variant names:

• chr22-19933614-C-T
• rs9605030
• NM_006440.5:c.104-2516G>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.104-2516G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 795,366 control chromosomes in the GnomAD database, including 7,034 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 0.11 (1188 hom., cov: 33)
  • Exomes 𝑓: 0.13 (5846 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 18 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)

ENSG00000289946 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.104-2516G>A		intron_variant	Intron 1 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.104-2516G>A		intron_variant	Intron 1 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16223 AN: 152150 Hom.: 1187 Cov.: 33

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.264

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.130

GnomAD4 exome AF: 0.130 AC: 83554 AN: 643098 Hom.: 5846 AF XY: 0.130 AC XY: 42046 AN XY: 323042

African (AFR) AF: 0.0216 AC: 296 AN: 13720

American (AMR) AF: 0.0994 AC: 1666 AN: 16756

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 2089 AN: 8522

East Asian (EAS) AF: 0.270 AC: 2703 AN: 10010

South Asian (SAS) AF: 0.113 AC: 6250 AN: 55514

European-Finnish (FIN) AF: 0.102 AC: 1035 AN: 10128

Middle Eastern (MID) AF: 0.181 AC: 299 AN: 1654

European-Non Finnish (NFE) AF: 0.131 AC: 65893 AN: 502506

Other (OTH) AF: 0.137 AC: 3323 AN: 24288

GnomAD4 genome AF: 0.106 AC: 16216 AN: 152268 Hom.: 1188 Cov.: 33 AF XY: 0.108 AC XY: 8060 AN XY: 74434

African (AFR) AF: 0.0271 AC: 1128 AN: 41576

American (AMR) AF: 0.114 AC: 1743 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 863 AN: 3470

East Asian (EAS) AF: 0.263 AC: 1356 AN: 5156

South Asian (SAS) AF: 0.119 AC: 573 AN: 4828

European-Finnish (FIN) AF: 0.101 AC: 1069 AN: 10600

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9057 AN: 68008

Other (OTH) AF: 0.128 AC: 271 AN: 2116

Alfa AF: 0.133 Hom.: 2879

Bravo AF: 0.105

Asia WGS AF: 0.173 AC: 602 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.68
PhyloP100		-1.2
PromoterAI		-0.026	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: rs9605030; hg19: chr22-19921137;