22-19941504-C-T

Variant names:

• chr22-19941504-C-T
• rs13306278
• NM_006440.5:c.103+197G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006440.5(TXNRD2):​c.103+197G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 968,220 control chromosomes in the GnomAD database, including 8,813 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (986 hom., cov: 32)
  • Exomes 𝑓: 0.13 (7827 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.558
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 22-19941504-C-T is Benign according to our data. Variant chr22-19941504-C-T is described in ClinVar as Benign. ClinVar VariationId is 225950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.103+197G>A		intron_variant	Intron 1 of 17	ENST00000400521.7	NP_006431.2
TXNRD2	NM_001352300.2	c.103+197G>A		intron_variant	Intron 1 of 16		NP_001339229.1
TXNRD2	NM_001282512.3	c.103+197G>A		intron_variant	Intron 1 of 11		NP_001269441.1
TXNRD2	NR_147957.2	n.118+197G>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+197G>A		intron_variant	Intron 1 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.0981 AC: 14919 AN: 152110 Hom.: 986 Cov.: 32

Gnomad AFR AF: 0.0261

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.173

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0892

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.134 AC: 109051 AN: 815992 Hom.: 7827 AF XY: 0.135 AC XY: 53793 AN XY: 399372

African (AFR) AF: 0.0210 AC: 341 AN: 16270

American (AMR) AF: 0.0762 AC: 594 AN: 7794

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 2258 AN: 13008

East Asian (EAS) AF: 0.00639 AC: 155 AN: 24256

South Asian (SAS) AF: 0.159 AC: 5231 AN: 32868

European-Finnish (FIN) AF: 0.100 AC: 2664 AN: 26584

Middle Eastern (MID) AF: 0.157 AC: 390 AN: 2490

European-Non Finnish (NFE) AF: 0.141 AC: 92797 AN: 656568

Other (OTH) AF: 0.128 AC: 4621 AN: 36154

GnomAD4 genome AF: 0.0980 AC: 14921 AN: 152228 Hom.: 986 Cov.: 32 AF XY: 0.0958 AC XY: 7136 AN XY: 74452

African (AFR) AF: 0.0260 AC: 1079 AN: 41560

American (AMR) AF: 0.0957 AC: 1464 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.173 AC: 600 AN: 3472

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5170

South Asian (SAS) AF: 0.144 AC: 693 AN: 4820

European-Finnish (FIN) AF: 0.0892 AC: 947 AN: 10618

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9762 AN: 67972

Other (OTH) AF: 0.111 AC: 235 AN: 2112

Alfa AF: 0.120 Hom.: 152

Bravo AF: 0.0916

Asia WGS AF: 0.0850 AC: 297 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.0
DANN	Benign	0.88
PhyloP100		-0.56
PromoterAI		0.022	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: rs13306278; hg19: chr22-19929027;