chr22-19940569-G-A

Variant names:

Variant summary

Our verdict is The variant received -12 classification points (ACMG Germline Pathogenicity v2019): 0P and 12B. BA1BP4_Strong

The NM_006440.5(TXNRD2):c.103+1132C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.592 (AC=89,996) in the gnomAD database across 152,020 control chromosomes, including 26,853 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.694. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.59 ( 26853 hom., cov: 32)

Consequence

TXNRD2
NM_006440.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.830

Publications

86 publications found

Variant links:

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):

glucocorticoid deficiency 5
Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
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

TXNRD2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_006440.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6939 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_006440.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TXNRD2	NM_006440.5	MANE Select	c.103+1132C>T	intron	N/A	NP_006431.2
TXNRD2	NM_001352300.2		c.103+1132C>T	intron	N/A	NP_001339229.1
TXNRD2	NM_001282512.3		c.103+1132C>T	intron	N/A	NP_001269441.1	E7EWK1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.103+1132C>T	intron	N/A	ENSP00000383365.1	Q9NNW7-1
TXNRD2	ENST00000400519.6	TSL:1	c.103+1132C>T	intron	N/A	ENSP00000383363.1	A0A182DWF3
TXNRD2	ENST00000334363.14	TSL:1	c.103+1132C>T	intron	N/A	ENSP00000334451.9	E7EWK1

Frequencies

GnomAD3 genomes

AF:

0.592

AC:

89907

AN:

151902

Hom.:

26817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.616

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.658

Gnomad ASJ

AF:

0.707

Gnomad EAS

AF:

0.714

Gnomad SAS

AF:

0.636

Gnomad FIN

AF:

0.479

Gnomad MID

AF:

0.601

Gnomad NFE

AF:

0.561

Gnomad OTH

AF:

0.630

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

GnomAD4 genome

AF:

0.592

AC:

89996

AN:

152020

Hom.:

26853

Cov.:

AF XY:

0.594

AC XY:

44137

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.617

AC:

25558

AN:

41442

American (AMR)

AF:

0.658

AC:

10060

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.707

AC:

2453

AN:

3472

East Asian (EAS)

AF:

0.713

AC:

3687

AN:

5170

South Asian (SAS)

AF:

0.637

AC:

3068

AN:

4820

European-Finnish (FIN)

AF:

0.479

AC:

5056

AN:

10546

Middle Eastern (MID)

AF:

0.592

AC:

174

AN:

294

European-Non Finnish (NFE)

AF:

0.561

AC:

38158

AN:

67962

Other (OTH)

AF:

0.632

AC:

1336

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1873

3745

5618

7490

9363

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.567

Hom.:

3040

Bravo

AF:

0.605

Asia WGS

AF:

0.671

AC:

2334

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.701

AC:

85918

AN:

122626

Turkish Variome

AF:

0.641

AC:

991

AN:

1546

Hom.:

328

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.703

AC:

6296

AN:

8960

Hom.:

2205

ABraOM SABE-WGS-1171

AF:

0.659

AC:

1544

AN:

2342

Hom.:

504

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

1.4

(source)

DANN

Benign

0.58

PhyloP100

-0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over