rs2020917

Variant names:

• chr22-19941361-C-T
• rs2020917
• NM_006440.5:c.103+340G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006440.5(TXNRD2):​c.103+340G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 152,078 control chromosomes in the GnomAD database, including 4,163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.22 (4163 hom., cov: 32)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.99

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-19941361-C-T is Benign according to our data. Variant chr22-19941361-C-T is described in ClinVar as [Benign]. Clinvar id is 1169562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.103+340G>A		intron_variant	Intron 1 of 17	ENST00000400521.7	NP_006431.2
TXNRD2	NM_001352300.2	c.103+340G>A		intron_variant	Intron 1 of 16		NP_001339229.1
TXNRD2	NM_001282512.3	c.103+340G>A		intron_variant	Intron 1 of 11		NP_001269441.1
TXNRD2	NR_147957.2	n.118+340G>A		intron_variant	Intron 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+340G>A		intron_variant	Intron 1 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33772 AN: 151960 Hom.: 4161 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.248

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.222 AC: 33773 AN: 152078 Hom.: 4163 Cov.: 32 AF XY: 0.221 AC XY: 16425 AN XY: 74356

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.426

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.249

Alfa AF: 0.279 Hom.: 7212

Bravo AF: 0.216

Asia WGS AF: 0.263 AC: 916 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs2020917; hg19: chr22-19928884; COSMIC: COSV57635895; COSMIC: COSV57635895;