rs1060501404

Positions:

• chr22-19941752-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000400521.7(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 ENST00000400521.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.52C>T	p.Arg18Trp	missense_variant	1/18	ENST00000400521.7	NP_006431.2
COMT	NM_000754.4			upstream_gene_variant		ENST00000361682.11	NP_000745.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.52C>T	p.Arg18Trp	missense_variant	1/18	1	NM_006440.5	ENSP00000383365	P4
COMT	ENST00000361682.11			upstream_gene_variant		1	NM_000754.4	ENSP00000354511	P2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.37e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TXNRD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 407093). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces arginine with tryptophan at codon 18 of the TXNRD2 protein (p.Arg18Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	.;.;N;.
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.018	D;D;T;D
Polyphen		0.96, 0.99	.;.;D;D
Vest4		0.40
MutPred		0.56		Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);Loss of disorder (P = 0.0064);
MVP		0.74
MPC		0.54
ClinPred		0.61	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501404; hg19: chr22-19929275;