22-19941705-TGCGCCCCGCGCC-T

Variant names:

• chr22-19941705-TGCGCCCCGCGCC-T
• rs766448975
• NM_006440.5:c.87_98delGGCGCGGGGCGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_006440.5(TXNRD2):​c.87_98delGGCGCGGGGCGC​(p.Ala30_Ala33del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000566 in 1,483,316 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.58

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]

COMT (HGNC:2228): (catechol-O-methyltransferase) Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. COMT is found in two forms in tissues, a soluble form (S-COMT) and a membrane-bound form (MB-COMT). The differences between S-COMT and MB-COMT reside within the N-termini. Several transcript variants are formed through the use of alternative translation initiation sites and promoters. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_006440.5

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 18	ENST00000400521.7	NP_006431.2
TXNRD2	NM_001352300.2	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 17		NP_001339229.1
TXNRD2	NM_001282512.3	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 12		NP_001269441.1
TXNRD2	NR_147957.2	n.102_113delGGCGCGGGGCGC		non_coding_transcript_exon_variant	Exon 1 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 18	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000674 AC: 6 AN: 88996 Hom.: 0 AF XY: 0.0000198 AC XY: 1 AN XY: 50384

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000595

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000481 AC: 64 AN: 1331280 Hom.: 0 AF XY: 0.0000487 AC XY: 32 AN XY: 656468

Gnomad4 AFR exome AF: 0.000522

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.0000271

Gnomad4 FIN exome AF: 0.0000302

Gnomad4 NFE exome AF: 0.0000275

Gnomad4 OTH exome AF: 0.0000724

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74292

Gnomad4 AFR AF: 0.000411

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Aug 06, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In-frame deletion of 4 amino acids in a repeat region; In silico analysis supports that this variant does not alter protein structure/function -

Primary dilated cardiomyopathy Uncertain:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.87_98del, results in the deletion of 4 amino acid(s) of the TXNRD2 protein (p.Ala30_Ala33del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766448975, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TXNRD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1497519). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Jul 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.87_98del12 variant (also known as p.R31_A34del) is located in coding exon 1 of the TXNRD2 gene. This variant results from an in-frame deletion of 12 nucleotides at positions 87 to 98. This results in the deletion of 4 amino acids between codons 31 and 34. These amino acid positions are not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs766448975; hg19: chr22-19929228;