chr22-19941683-G-GC

Position:

• chr22-19941683-G-GC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_006440.5(TXNRD2):​c.103+17_103+18insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,467,128 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 22-19941683-G-GC is Benign according to our data. Variant chr22-19941683-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 422808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5	c.103+17_103+18insG		intron_variant		ENST00000400521.7
TXNRD2	NM_001282512.3	c.103+17_103+18insG		intron_variant
TXNRD2	NM_001352300.2	c.103+17_103+18insG		intron_variant
TXNRD2	NR_147957.2	n.118+17_118+18insG		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7	c.103+17_103+18insG		intron_variant		1	NM_006440.5	P4

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000205 AC: 16 AN: 77990 Hom.: 0 AF XY: 0.000156 AC XY: 7 AN XY: 44968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000359

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000437 AC: 575 AN: 1314970 Hom.: 1 Cov.: 31 AF XY: 0.000430 AC XY: 279 AN XY: 648546

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000447

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000140

Gnomad4 FIN exome AF: 0.0000305

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.000275

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74346

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000972 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2017

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. -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs756452923; hg19: chr22-19929206;