Genetic Variant NM_006440.5:c.763G>C (chr22-19898050-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006440.5(TXNRD2):c.763G>C(p.Gly255Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000857 in 1,557,312 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G255S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00046 ( 2 hom. )

Consequence

TXNRD2
NM_006440.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.36

Publications

2 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):

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)

TXNRD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.018730104).

BP6

Variant 22-19898050-C-G is Benign according to our data. Variant chr22-19898050-C-G is described in ClinVar as Benign. ClinVar VariationId is 264489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000456 (640/1404960) while in subpopulation AFR AF = 0.0169 (540/31872). AF 95% confidence interval is 0.0158. There are 2 homozygotes in GnomAdExome4. There are 267 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AD,AR,Unknown gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TXNRD2	NM_006440.5	MANE Select	c.763G>C	p.Gly255Arg	missense	Exon 10 of 18	NP_006431.2
TXNRD2	NM_001352300.2		c.760G>C	p.Gly254Arg	missense	Exon 10 of 17	NP_001339229.1
TXNRD2	NM_001352301.2		c.673G>C	p.Gly225Arg	missense	Exon 10 of 18	NP_001339230.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TXNRD2	ENST00000400521.7	TSL:1 MANE Select	c.763G>C	p.Gly255Arg	missense	Exon 10 of 18	ENSP00000383365.1
TXNRD2	ENST00000400519.6	TSL:1	c.760G>C	p.Gly254Arg	missense	Exon 10 of 17	ENSP00000383363.1
TXNRD2	ENST00000400518.5	TSL:1	c.673G>C	p.Gly225Arg	missense	Exon 10 of 18	ENSP00000383362.1

Frequencies

GnomAD3 genomes

AF:

0.00457

AC:

695

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.000147

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.000819

AC:

134

AN:

163530

AF XY:

0.000631

show subpopulations

Gnomad AFR exome

AF:

0.0130

Gnomad AMR exome

AF:

0.000664

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000453

Gnomad OTH exome

AF:

0.000223

GnomAD4 exome

AF:

0.000456

AC:

640

AN:

1404960

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

267

AN XY:

693724

show subpopulations

African (AFR)

AF:

0.0169

AC:

540

AN:

31872

American (AMR)

AF:

0.000847

AC:

AN:

36590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25246

East Asian (EAS)

AF:

0.00

AC:

AN:

36102

South Asian (SAS)

AF:

0.0000251

AC:

AN:

79580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48584

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1083030

Other (OTH)

AF:

0.000841

AC:

AN:

58272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00456

AC:

694

AN:

152352

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

325

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0160

AC:

665

AN:

41580

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68040

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000210

Hom.:

Bravo

AF:

0.00483

ESP6500AA

AF:

0.00976

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000733

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 07, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Glucocorticoid deficiency 5

Benign:1

Sep 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary dilated cardiomyopathy

Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Nov 20, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.019

MetaSVM

Uncertain

-0.077

MutationAssessor

Pathogenic

3.2

PhyloP100

4.4

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-7.4

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.56

MVP

0.75

MPC

0.83

ClinPred

0.064

GERP RS

4.4

Varity_R

0.87

Mutation Taster

=92/8

polymorphism

(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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over