rs766448975

Variant names:

• chr22-19941705-TGCGCCCCGCGCC-T
• rs766448975
• NM_006440.5:c.87_98delGGCGCGGGGCGC

Your query was ambiguous. Multiple possible variants found:

• chr22-19941705-TGCGCCCCGCGCC-T
• chr22-19941705-TGCGCCCCGCGCC-TGCGCCCCGCGCCGCGCCCCGCGCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_006440.5(TXNRD2):​c.87_98delGGCGCGGGGCGC​(p.Ala30_Ala33del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000566 in 1,483,316 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: TXNRD2 NM_006440.5 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.58
• 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 -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_006440.5

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.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 18	NP_006431.2
	TXNRD2	NM_001352300.2		c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 17	NP_001339229.1
	TXNRD2	NM_001282512.3		c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	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.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 18	ENSP00000383365.1	Q9NNW7-1
	TXNRD2	ENST00000400519.6	TSL:1	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 17	ENSP00000383363.1	A0A182DWF3
	TXNRD2	ENST00000334363.14	TSL:1	c.87_98delGGCGCGGGGCGC	p.Ala30_Ala33del	disruptive_inframe_deletion	Exon 1 of 12	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000674 AC: 6 AN: 88996 AF XY: 0.0000198

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000595

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000481 AC: 64 AN: 1331280 Hom.: 0 AF XY: 0.0000487 AC XY: 32 AN XY: 656468

African (AFR) AF: 0.000522 AC: 14 AN: 26804

American (AMR) AF: 0.000312 AC: 9 AN: 28836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23162

East Asian (EAS) AF: 0.000166 AC: 5 AN: 30170

South Asian (SAS) AF: 0.0000271 AC: 2 AN: 73894

European-Finnish (FIN) AF: 0.0000302 AC: 1 AN: 33126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3908

European-Non Finnish (NFE) AF: 0.0000275 AC: 29 AN: 1056168

Other (OTH) AF: 0.0000724 AC: 4 AN: 55212

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74292

African (AFR) AF: 0.000411 AC: 17 AN: 41406

American (AMR) AF: 0.0000655 AC: 1 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000159

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=148/52	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766448975; hg19: chr22-19929228;