22-19876812-G-A

Variant names:

• chr22-19876812-G-A
• rs7287073
• ENST00000400519.6:c.*293C>T

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.*65+228C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 313,650 control chromosomes in the GnomAD database, including 2,706 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1156 hom., cov: 33)
  • Exomes 𝑓: 0.12 (1550 hom.)
• Consequence: TXNRD2 NM_006440.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.370
• Publications: 5 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]

TXNRD2 Gene-Disease associations (from GenCC):

• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial glucocorticoid deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• glucocorticoid deficiency 5

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 22-19876812-G-A is Benign according to our data. Variant chr22-19876812-G-A is described in ClinVar as [Benign]. Clinvar id is 1298115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNRD2	NM_006440.5	c.*65+228C>T		intron_variant	Intron 17 of 17	ENST00000400521.7	NP_006431.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNRD2	ENST00000400521.7	c.*65+228C>T		intron_variant	Intron 17 of 17	1	NM_006440.5	ENSP00000383365.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17011 AN: 152094 Hom.: 1152 Cov.: 33

Gnomad AFR AF: 0.0551

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.0100

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0921

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.124 AC: 20012 AN: 161438 Hom.: 1550 Cov.: 2 AF XY: 0.125 AC XY: 10260 AN XY: 81766

African (AFR) AF: 0.0508 AC: 302 AN: 5946

American (AMR) AF: 0.0886 AC: 619 AN: 6988

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 1234 AN: 6228

East Asian (EAS) AF: 0.00579 AC: 83 AN: 14326

South Asian (SAS) AF: 0.0911 AC: 410 AN: 4502

European-Finnish (FIN) AF: 0.0898 AC: 1010 AN: 11246

Middle Eastern (MID) AF: 0.180 AC: 158 AN: 880

European-Non Finnish (NFE) AF: 0.148 AC: 14875 AN: 100592

Other (OTH) AF: 0.123 AC: 1321 AN: 10730

GnomAD4 genome AF: 0.112 AC: 17040 AN: 152212 Hom.: 1156 Cov.: 33 AF XY: 0.109 AC XY: 8137 AN XY: 74428

African (AFR) AF: 0.0554 AC: 2303 AN: 41534

American (AMR) AF: 0.107 AC: 1632 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 701 AN: 3468

East Asian (EAS) AF: 0.0100 AC: 52 AN: 5178

South Asian (SAS) AF: 0.103 AC: 499 AN: 4830

European-Finnish (FIN) AF: 0.0921 AC: 978 AN: 10618

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10435 AN: 67976

Other (OTH) AF: 0.120 AC: 254 AN: 2112

Alfa AF: 0.127 Hom.: 184

Bravo AF: 0.108

Asia WGS AF: 0.0670 AC: 232 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.0
DANN	Benign	0.62
PhyloP100		0.37
Mutation Taster		=97/3	polymorphism (auto)

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: rs7287073; hg19: chr22-19864335; COSMIC: COSV68692950;