NM_006440.5:c.103+17delG

Variant names:

• chr22-19941683-GC-G
• rs756452923
• NM_006440.5:c.103+17delG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006440.5(TXNRD2):​c.103+17delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,314,970 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.115
• 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]

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]

COMT Gene-Disease associations (from GenCC):

• paroxysmal dyskinesia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.103+17delG		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.103+17delG		intron	N/A	NP_001339229.1
	TXNRD2	NM_001282512.3		c.103+17delG		intron	N/A	NP_001269441.1	E7EWK1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.103+17delG		intron	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.103+17delG		intron	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.103+17delG		intron	N/A	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.60e-7 AC: 1 AN: 1314970 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 648548

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26242

American (AMR) AF: 0.00 AC: 0 AN: 25118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22354

East Asian (EAS) AF: 0.00 AC: 0 AN: 29378

South Asian (SAS) AF: 0.00 AC: 0 AN: 71618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3854

European-Non Finnish (NFE) AF: 9.53e-7 AC: 1 AN: 1049164

Other (OTH) AF: 0.00 AC: 0 AN: 54462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs756452923; hg19: chr22-19929206;