22-19919556-TTC-CTT

Variant names:

• chr22-19919556-TTC-CTT
• NM_006440.5:c.214_216delGAAinsAAG
• TXNRD2 p.Glu72Lys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006440.5(TXNRD2):​c.214_216delGAAinsAAG​(p.Glu72Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 27)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.33
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.214_216delGAAinsAAG	p.Glu72Lys	missense	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.211_213delGAAinsAAG	p.Glu71Lys	missense	N/A	NP_001339229.1
	TXNRD2	NM_001352301.2		c.124_126delGAAinsAAG	p.Glu42Lys	missense	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.214_216delGAAinsAAG	p.Glu72Lys	missense	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.211_213delGAAinsAAG	p.Glu71Lys	missense	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000400518.5	TSL:1	c.124_126delGAAinsAAG	p.Glu42Lys	missense	N/A	ENSP00000383362.1	A0A182DWF2

Frequencies

GnomAD3 genomes Cov.: 27

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

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-19907079;