chr22-19880705-G-A

Position:

chr22-19880705-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006440.5(TXNRD2):c.1099C>T(p.Leu367=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,612,016 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 40 hom., cov: 33)

Exomes 𝑓: 0.0041 ( 55 hom. )

Consequence

TXNRD2
NM_006440.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 22-19880705-G-A is Benign according to our data. Variant chr22-19880705-G-A is described in ClinVar as [Benign]. Clinvar id is 263358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-19880705-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2235/151290) while in subpopulation AFR AF= 0.043 (1758/40864). AF 95% confidence interval is 0.0413. There are 40 homozygotes in gnomad4. There are 1049 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TXNRD2	NM_006440.5 linkuse as main transcript	c.1099C>T	p.Leu367=	synonymous_variant	13/18	ENST00000400521.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TXNRD2	ENST00000400521.7 linkuse as main transcript	c.1099C>T	p.Leu367=	synonymous_variant	13/18	1	NM_006440.5	P4	Q9NNW7-1

Frequencies

GnomAD3 genomes

AF:

0.0148

AC:

2231

AN:

151176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0139

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.00321

Gnomad OTH

AF:

0.0159

GnomAD3 exomes

AF:

0.00660

AC:

1635

AN:

247832

Hom.:

AF XY:

0.00595

AC XY:

804

AN XY:

135014

show subpopulations

Gnomad AFR exome

AF:

0.0470

Gnomad AMR exome

AF:

0.00670

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000850

Gnomad FIN exome

AF:

0.000608

Gnomad NFE exome

AF:

0.00401

Gnomad OTH exome

AF:

0.00748

GnomAD4 exome

AF:

0.00410

AC:

5993

AN:

1460726

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

2827

AN XY:

726684

show subpopulations

Gnomad4 AFR exome

AF:

0.0476

Gnomad4 AMR exome

AF:

0.00734

Gnomad4 ASJ exome

AF:

0.0163

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.000726

Gnomad4 NFE exome

AF:

0.00269

Gnomad4 OTH exome

AF:

0.00754

GnomAD4 genome

AF:

0.0148

AC:

2235

AN:

151290

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1049

AN XY:

73974

show subpopulations

Gnomad4 AFR

AF:

0.0430

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.0139

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00321

Gnomad4 OTH

AF:

0.0158

Alfa

AF:

0.00947

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00356

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2016

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Primary dilated cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2015

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over