22-19941740-C-T

Variant names:

• chr22-19941740-C-T
• rs370819229
• NM_006440.5:c.64G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006440.5(TXNRD2):​c.64G>A​(p.Val22Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,494,506 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5 O:1
• Conservation: PhyloP100: -0.430
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048235953).
• BP6: Variant 22-19941740-C-T is Benign according to our data. Variant chr22-19941740-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 391644.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR,Unknown gene

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.64G>A	p.Val22Met	missense	Exon 1 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.64G>A	p.Val22Met	missense	Exon 1 of 17	NP_001339229.1
	TXNRD2	NM_001282512.3		c.64G>A	p.Val22Met	missense	Exon 1 of 12	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.64G>A	p.Val22Met	missense	Exon 1 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.64G>A	p.Val22Met	missense	Exon 1 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.64G>A	p.Val22Met	missense	Exon 1 of 12	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000730 AC: 73 AN: 99958 AF XY: 0.000656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000658

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000184

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00108 AC: 1453 AN: 1342260 Hom.: 5 Cov.: 31 AF XY: 0.00105 AC XY: 694 AN XY: 662370

African (AFR) AF: 0.000221 AC: 6 AN: 27106

American (AMR) AF: 0.000770 AC: 24 AN: 31186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23600

East Asian (EAS) AF: 0.00 AC: 0 AN: 30696

South Asian (SAS) AF: 0.00 AC: 0 AN: 74842

European-Finnish (FIN) AF: 0.000180 AC: 6 AN: 33424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3962

European-Non Finnish (NFE) AF: 0.00127 AC: 1351 AN: 1061796

Other (OTH) AF: 0.00119 AC: 66 AN: 55648

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000457 AC XY: 34 AN XY: 74448

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 67986

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.000646

ESP6500AA AF: 0.00114 AC: 2

ESP6500EA AF: 0.00133 AC: 6

ExAC AF: 0.000429 AC: 40

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Primary dilated cardiomyopathy (1)
-	1	-	TXNRD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.1
DANN	Benign	0.97
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.43
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.45	N
REVEL	Benign	0.054
Sift	Benign	0.19	T
Sift4G	Benign	0.27	T
Polyphen		0.59	P
Vest4		0.14
MVP		0.39
MPC		0.21
ClinPred		0.034	T
GERP RS		-2.8
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
Varity_R		0.036
Mutation Taster		=298/2	polymorphism

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: rs370819229; hg19: chr22-19929263;