NM_006440.5:c.949+5419T>A

Variant names:

• chr22-19889988-A-T
• rs9606173
• NM_006440.5:c.949+5419T>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.949+5419T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,128 control chromosomes in the GnomAD database, including 2,338 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 0.17 (2338 hom., cov: 33)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	NM_006440.5	MANE Select	c.949+5419T>A		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.946+5419T>A		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.859+5419T>A		intron	N/A	NP_001339230.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.949+5419T>A		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.946+5419T>A		intron	N/A	ENSP00000383363.1
	TXNRD2	ENST00000400518.5	TSL:1	c.859+5419T>A		intron	N/A	ENSP00000383362.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26430 AN: 152010 Hom.: 2334 Cov.: 33

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.219

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.156

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

GnomAD4 genome AF: 0.174 AC: 26461 AN: 152128 Hom.: 2338 Cov.: 33 AF XY: 0.177 AC XY: 13176 AN XY: 74352

African (AFR) AF: 0.179 AC: 7431 AN: 41494

American (AMR) AF: 0.198 AC: 3020 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 462 AN: 3470

East Asian (EAS) AF: 0.204 AC: 1058 AN: 5176

South Asian (SAS) AF: 0.183 AC: 881 AN: 4826

European-Finnish (FIN) AF: 0.219 AC: 2308 AN: 10558

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10832 AN: 68004

Other (OTH) AF: 0.156 AC: 330 AN: 2110

Alfa AF: 0.165 Hom.: 248

Bravo AF: 0.172

Asia WGS AF: 0.217 AC: 753 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.090
DANN	Benign	0.45
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs9606173; hg19: chr22-19877511;