22-19941727-A-G

Variant names:

• chr22-19941727-A-G
• rs925920723
• NM_006440.5:c.77T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006440.5(TXNRD2):​c.77T>C​(p.Val26Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,487,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. V26G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.625
• 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039695084).

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.77T>C	p.Val26Ala	missense	Exon 1 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.77T>C	p.Val26Ala	missense	Exon 1 of 17	NP_001339229.1
	TXNRD2	NM_001282512.3		c.77T>C	p.Val26Ala	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.77T>C	p.Val26Ala	missense	Exon 1 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.77T>C	p.Val26Ala	missense	Exon 1 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.77T>C	p.Val26Ala	missense	Exon 1 of 12	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151770 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 1 AN: 91588 AF XY: 0.0000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000185

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000539 AC: 72 AN: 1335474 Hom.: 0 Cov.: 31 AF XY: 0.0000531 AC XY: 35 AN XY: 658686

African (AFR) AF: 0.0000371 AC: 1 AN: 26938

American (AMR) AF: 0.00 AC: 0 AN: 29596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23392

East Asian (EAS) AF: 0.0000657 AC: 2 AN: 30428

South Asian (SAS) AF: 0.00 AC: 0 AN: 74348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.0000652 AC: 69 AN: 1058174

Other (OTH) AF: 0.00 AC: 0 AN: 55436

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151770 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74136

African (AFR) AF: 0.0000242 AC: 1 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67834

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.3
DANN	Benign	0.89
DEOGEN2	Benign	0.064	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.63
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.049
Sift	Benign	0.22	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.096
MutPred		0.39		Gain of disorder (P = 0.0323)
MVP		0.17
MPC		0.25
ClinPred		0.0099	T
GERP RS		-1.2
PromoterAI		0.51	Over-expression
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.6
Varity_R		0.022
Mutation Taster		=82/18	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: rs925920723; hg19: chr22-19929250;