rs3788317

Variant names:

• chr22-19902302-G-T
• rs3788317
• NM_006440.5:c.663-3234C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_006440.5(TXNRD2):​c.663-3234C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,166 control chromosomes in the GnomAD database, including 7,892 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 0.30 (7892 hom., cov: 34)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03
• 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)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.479 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.663-3234C>A		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.660-3234C>A		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.573-3234C>A		intron	N/A	NP_001339230.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.663-3234C>A		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.660-3234C>A		intron	N/A	ENSP00000383363.1
	TXNRD2	ENST00000400518.5	TSL:1	c.573-3234C>A		intron	N/A	ENSP00000383362.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45246 AN: 152048 Hom.: 7858 Cov.: 34

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.277

Gnomad ASJ AF: 0.257

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.298 AC: 45344 AN: 152166 Hom.: 7892 Cov.: 34 AF XY: 0.292 AC XY: 21730 AN XY: 74372

African (AFR) AF: 0.485 AC: 20112 AN: 41488

American (AMR) AF: 0.277 AC: 4238 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.257 AC: 890 AN: 3468

East Asian (EAS) AF: 0.174 AC: 897 AN: 5170

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4828

European-Finnish (FIN) AF: 0.167 AC: 1769 AN: 10596

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

European-Non Finnish (NFE) AF: 0.228 AC: 15515 AN: 68006

Other (OTH) AF: 0.287 AC: 606 AN: 2114

Alfa AF: 0.257 Hom.: 18935

Bravo AF: 0.315

Asia WGS AF: 0.279 AC: 968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.74
PhyloP100		1.0
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: rs3788317; hg19: chr22-19889825; COSMIC: COSV57635408; COSMIC: COSV57635408;