22-19941684-C-A

Variant names:

• chr22-19941684-C-A
• NM_006440.5:c.103+17G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006440.5(TXNRD2):​c.103+17G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000756 in 1,323,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-19941684-C-A is Benign according to our data. Variant chr22-19941684-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2762247.Status of the report is criteria_provided_single_submitter, 1 stars.

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+17G>T		intron	N/A	NP_006431.2
	TXNRD2	NM_001352300.2		c.103+17G>T		intron	N/A	NP_001339229.1
	TXNRD2	NM_001282512.3		c.103+17G>T		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+17G>T		intron	N/A	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.103+17G>T		intron	N/A	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.103+17G>T		intron	N/A	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.56e-7 AC: 1 AN: 1323348 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 652624

African (AFR) AF: 0.00 AC: 0 AN: 26514

American (AMR) AF: 0.00 AC: 0 AN: 27180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22676

East Asian (EAS) AF: 0.00 AC: 0 AN: 29692

South Asian (SAS) AF: 0.00 AC: 0 AN: 72732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3882

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1052812

Other (OTH) AF: 0.00 AC: 0 AN: 54894

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.0
DANN	Benign	0.88
PhyloP100		-0.12
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr22-19929207;