rs4646310

Variant names:

• chr22-19941283-G-A
• rs4646310
• NM_006440.5:c.103+418C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-19941283-G-A
• chr22-19941283-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006440.5(TXNRD2):​c.103+418C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 152,190 control chromosomes in the GnomAD database, including 1,906 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1906 hom., cov: 32)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.650
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.103+418C>T		intron_variant	Intron 1 of 17	ENST00000400521.7	NP_006431.2
TXNRD2	NM_001352300.2	c.103+418C>T		intron_variant	Intron 1 of 16		NP_001339229.1
TXNRD2	NM_001282512.3	c.103+418C>T		intron_variant	Intron 1 of 11		NP_001269441.1
TXNRD2	NR_147957.2	n.118+418C>T		intron_variant	Intron 1 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+418C>T		intron_variant	Intron 1 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21966 AN: 152072 Hom.: 1907 Cov.: 32

Gnomad AFR AF: 0.0746

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0307

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.190

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.144 AC: 21971 AN: 152190 Hom.: 1906 Cov.: 32 AF XY: 0.141 AC XY: 10510 AN XY: 74412

African (AFR) AF: 0.0747 AC: 3103 AN: 41530

American (AMR) AF: 0.144 AC: 2203 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 726 AN: 3462

East Asian (EAS) AF: 0.0307 AC: 159 AN: 5174

South Asian (SAS) AF: 0.124 AC: 600 AN: 4824

European-Finnish (FIN) AF: 0.150 AC: 1586 AN: 10606

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.190 AC: 12933 AN: 67988

Other (OTH) AF: 0.164 AC: 348 AN: 2116

Alfa AF: 0.177 Hom.: 4142

Bravo AF: 0.142

Asia WGS AF: 0.0620 AC: 217 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.98
DANN	Benign	0.65
PhyloP100		-0.65
PromoterAI		0.00010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4646310; hg19: chr22-19928806;