rs269868

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014080.5(DUOX2):c.3200C>T(p.Ser1067Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,613,952 control chromosomes in the GnomAD database, including 655,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.73 ( 47658 hom., cov: 32)

Exomes 𝑓: 0.91 ( 607648 hom. )

Consequence

DUOX2
NM_014080.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.05

Publications

49 publications found

Variant links:

Genes affected

DUOX2 (HGNC:13273): (dual oxidase 2) The protein encoded by this gene is a glycoprotein and a member of the NADPH oxidase family. The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. This complex contains an iodide transporter, thyroperoxidase, and a peroxide generating system that includes this encoded protein and DUOX1. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. [provided by RefSeq, Jul 2008]

DUOX2 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DUOX2 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=9.628715E-7).

BP6

Variant 15-45099877-G-A is Benign according to our data. Variant chr15-45099877-G-A is described in ClinVar as Benign. ClinVar VariationId is 260323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014080.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.3200C>T	p.Ser1067Leu	missense	Exon 25 of 34	NP_001350640.1
	DUOX2	NM_014080.5		c.3200C>T	p.Ser1067Leu	missense	Exon 25 of 34	NP_054799.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.3200C>T	p.Ser1067Leu	missense	Exon 25 of 34	ENSP00000373691.7
DUOX2	ENST00000603300.1	TSL:1	c.3200C>T	p.Ser1067Leu	missense	Exon 25 of 34	ENSP00000475084.1
DUOX2	ENST00000558383.1	TSL:5	n.5972C>T		non_coding_transcript_exon	Exon 16 of 17

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111516

AN:

151994

Hom.:

47671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.855

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

0.945

Gnomad SAS

AF:

0.944

Gnomad FIN

AF:

0.921

Gnomad MID

AF:

0.873

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.790

GnomAD2 exomes

AF:

0.875

AC:

219774

AN:

251092

AF XY:

0.890

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.865

Gnomad ASJ exome

AF:

0.928

Gnomad EAS exome

AF:

0.947

Gnomad FIN exome

AF:

0.929

Gnomad NFE exome

AF:

0.924

Gnomad OTH exome

AF:

0.901

GnomAD4 exome

AF:

0.905

AC:

1323562

AN:

1461838

Hom.:

607648

Cov.:

AF XY:

0.909

AC XY:

660817

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.236

AC:

7892

AN:

33476

American (AMR)

AF:

0.862

AC:

38530

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.930

AC:

24300

AN:

26136

East Asian (EAS)

AF:

0.943

AC:

37429

AN:

39700

South Asian (SAS)

AF:

0.940

AC:

81082

AN:

86256

European-Finnish (FIN)

AF:

0.929

AC:

49644

AN:

53416

Middle Eastern (MID)

AF:

0.903

AC:

5208

AN:

5768

European-Non Finnish (NFE)

AF:

0.923

AC:

1026172

AN:

1111982

Other (OTH)

AF:

0.883

AC:

53305

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

7264

14528

21793

29057

36321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21372

42744

64116

85488

106860

<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:

0.733

AC:

111506

AN:

152114

Hom.:

47658

Cov.:

AF XY:

0.742

AC XY:

55203

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.254

AC:

10540

AN:

41424

American (AMR)

AF:

0.855

AC:

13077

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.924

AC:

3205

AN:

3470

East Asian (EAS)

AF:

0.945

AC:

4878

AN:

5160

South Asian (SAS)

AF:

0.943

AC:

4548

AN:

4822

European-Finnish (FIN)

AF:

0.921

AC:

9773

AN:

10608

Middle Eastern (MID)

AF:

0.867

AC:

255

AN:

294

European-Non Finnish (NFE)

AF:

0.922

AC:

62695

AN:

68008

Other (OTH)

AF:

0.787

AC:

1665

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

841

1682

2524

3365

4206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.870

Hom.:

263394

Bravo

AF:

0.707

TwinsUK

AF:

0.927

AC:

3436

ALSPAC

AF:

0.919

AC:

3542

ESP6500AA

AF:

0.269

AC:

1182

ESP6500EA

AF:

0.925

AC:

7948

ExAC

AF:

0.864

AC:

104920

Asia WGS

AF:

0.854

AC:

2969

AN:

3478

EpiCase

AF:

0.924

EpiControl

AF:

0.931

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thyroid dyshormonogenesis 6 (4)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

MetaRNN

Benign

9.6e-7

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

PhyloP100

8.1

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.30

Sift

Benign

0.043

Sift4G

Benign

0.075

Polyphen

0.025

Vest4

0.23

MPC

0.057

ClinPred

0.045

GERP RS

5.6

Varity_R

0.31

gMVP

0.61

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Computational scores

Splicing

Publications

Other links and lift over