rs1060501404

Variant names:

• chr22-19941752-G-A
• rs1060501404
• NM_006440.5:c.52C>T

Variant summary

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

The NM_006440.5(TXNRD2):​c.52C>T​(p.Arg18Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000074 in 1,351,704 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06
• Publications: 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	NM_006440.5	MANE Select	c.52C>T	p.Arg18Trp	missense	Exon 1 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.52C>T	p.Arg18Trp	missense	Exon 1 of 17	NP_001339229.1
	TXNRD2	NM_001282512.3		c.52C>T	p.Arg18Trp	missense	Exon 1 of 12	NP_001269441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.52C>T	p.Arg18Trp	missense	Exon 1 of 18	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.52C>T	p.Arg18Trp	missense	Exon 1 of 17	ENSP00000383363.1
	TXNRD2	ENST00000334363.14	TSL:1	c.52C>T	p.Arg18Trp	missense	Exon 1 of 12	ENSP00000334451.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1351704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 667786

African (AFR) AF: 0.00 AC: 0 AN: 27388

American (AMR) AF: 0.00 AC: 0 AN: 33434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23800

East Asian (EAS) AF: 0.00 AC: 0 AN: 31156

South Asian (SAS) AF: 0.00 AC: 0 AN: 75550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 9.37e-7 AC: 1 AN: 1066700

Other (OTH) AF: 0.00 AC: 0 AN: 55968

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.0020	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.40
MutPred		0.56		Loss of disorder (P = 0.0064)
MVP		0.74
MPC		0.54
ClinPred		0.61	D
GERP RS		1.4
PromoterAI		-0.65	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.11
Mutation Taster		=81/19	polymorphism

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: rs1060501404; hg19: chr22-19929275;