rs925920723

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-19941727-A-C
• chr22-19941727-A-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_006440.5(TXNRD2):​c.77T>G​(p.Val26Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000444 in 1,487,352 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V26A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03216529).
• BP6: Variant 22-19941727-A-C is Benign according to our data. Variant chr22-19941727-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407094.

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>G	p.Val26Gly	missense	Exon 1 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.77T>G	p.Val26Gly	missense	Exon 1 of 17	NP_001339229.1
	TXNRD2	NM_001282512.3		c.77T>G	p.Val26Gly	missense	Exon 1 of 12	NP_001269441.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.77T>G	p.Val26Gly	missense	Exon 1 of 18	ENSP00000383365.1
	TXNRD2	ENST00000400519.6	TSL:1	c.77T>G	p.Val26Gly	missense	Exon 1 of 17	ENSP00000383363.1
	TXNRD2	ENST00000334363.14	TSL:1	c.77T>G	p.Val26Gly	missense	Exon 1 of 12	ENSP00000334451.9

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151770 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

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: 0.0000147

Gnomad OTH AF: 0.00

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

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 22 AN: 1335476 Hom.: 0 Cov.: 31 AF XY: 0.0000167 AC XY: 11 AN XY: 658686

African (AFR) AF: 0.000742 AC: 20 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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 1058176

Other (OTH) AF: 0.0000361 AC: 2 AN: 55436

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151876 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74252

African (AFR) AF: 0.00104 AC: 43 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15268

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67824

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	1	-	Glucocorticoid deficiency 5 (1)
-	1	-	not provided (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	8.6
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.63
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.047
Sift	Uncertain	0.018	D
Sift4G	Benign	0.49	T
Polyphen		0.0070	B
Vest4		0.19
MVP		0.21
MPC		0.27
ClinPred		0.044	T
GERP RS		-1.2
PromoterAI		0.72	Over-expression
Varity_R		0.15
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV57633961; COSMIC: COSV57633961;