rs5993853

Variant names:

• chr22-19892415-T-C
• rs5993853
• NM_006440.5:c.949+2992A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-19892415-T-C
• chr22-19892415-T-G

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+2992A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.781 in 152,288 control chromosomes in the GnomAD database, including 47,400 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 0.78 (47400 hom., cov: 35)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 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+2992A>G		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.946+2992A>G		intron	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.859+2992A>G		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+2992A>G		intron	N/A	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.946+2992A>G		intron	N/A	ENSP00000383363.1
	TXNRD2	ENST00000400518.5	TSL:1	c.859+2992A>G		intron	N/A	ENSP00000383362.1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118734 AN: 152170 Hom.: 47332 Cov.: 35

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.829

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.747

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

GnomAD4 genome AF: 0.781 AC: 118866 AN: 152288 Hom.: 47400 Cov.: 35 AF XY: 0.783 AC XY: 58314 AN XY: 74460

African (AFR) AF: 0.940 AC: 39080 AN: 41580

American (AMR) AF: 0.802 AC: 12284 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2437 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4812 AN: 5180

South Asian (SAS) AF: 0.830 AC: 4010 AN: 4834

European-Finnish (FIN) AF: 0.702 AC: 7434 AN: 10588

Middle Eastern (MID) AF: 0.616 AC: 180 AN: 292

European-Non Finnish (NFE) AF: 0.682 AC: 46410 AN: 68002

Other (OTH) AF: 0.748 AC: 1582 AN: 2114

Alfa AF: 0.712 Hom.: 39475

Bravo AF: 0.795

Asia WGS AF: 0.866 AC: 3010 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.6
DANN	Benign	0.63
PhyloP100		-1.4
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: rs5993853; hg19: chr22-19879938; COSMIC: COSV57635866; COSMIC: COSV57635866;