22-19941618-T-TG

Variant names:

• chr22-19941618-T-TG
• rs45511293
• NM_006440.5:c.103+82dupC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006440.5(TXNRD2):​c.103+82dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,360,916 control chromosomes in the GnomAD database, including 560 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (362 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (198 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 22-19941618-T-TG is Benign according to our data. Variant chr22-19941618-T-TG is described in ClinVar as Benign. ClinVar VariationId is 679107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 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.103+82dupC		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.103+82dupC		intron	N/A	NP_001339229.1
	TXNRD2	NM_001282512.3		c.103+82dupC		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+82_103+83insC		intron	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.103+82_103+83insC		intron	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.103+82_103+83insC		intron	N/A	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes AF: 0.0368 AC: 5593 AN: 152060 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.00311 AC: 3755 AN: 1208738 Hom.: 198 Cov.: 31 AF XY: 0.00268 AC XY: 1581 AN XY: 589174

African (AFR) AF: 0.129 AC: 3044 AN: 23560

American (AMR) AF: 0.0112 AC: 108 AN: 9670

Ashkenazi Jewish (ASJ) AF: 0.0000615 AC: 1 AN: 16264

East Asian (EAS) AF: 0.00 AC: 0 AN: 27060

South Asian (SAS) AF: 0.000218 AC: 11 AN: 50570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28794

Middle Eastern (MID) AF: 0.00561 AC: 19 AN: 3384

European-Non Finnish (NFE) AF: 0.000182 AC: 182 AN: 999910

Other (OTH) AF: 0.00787 AC: 390 AN: 49526

GnomAD4 genome AF: 0.0368 AC: 5600 AN: 152178 Hom.: 362 Cov.: 32 AF XY: 0.0357 AC XY: 2659 AN XY: 74410

African (AFR) AF: 0.127 AC: 5280 AN: 41514

American (AMR) AF: 0.0156 AC: 239 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67986

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0283 Hom.: 24

Bravo AF: 0.0418

Asia WGS AF: 0.00491 AC: 18 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
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: rs45511293; hg19: chr22-19929141;