rs2001616

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_001363711.2(DUOX2):c.413C>T(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,194 control chromosomes in the GnomAD database, including 48,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.77 ( 48317 hom., cov: 33)

Exomes 𝑓: 0.89 ( 585879 hom. )

Failed GnomAD Quality Control

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.47

Publications

34 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=1.5484195E-6).

BP6

Variant 15-45111868-G-A is Benign according to our data. Variant chr15-45111868-G-A is described in ClinVar as Benign. ClinVar VariationId is 260326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.456C>T		non_coding_transcript_exon_variant	Exon 4 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.766

AC:

116562

AN:

152076

Hom.:

48324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.417

Gnomad AMI

AF:

0.898

Gnomad AMR

AF:

0.857

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.909

Gnomad SAS

AF:

0.930

Gnomad FIN

AF:

0.911

Gnomad MID

AF:

0.863

Gnomad NFE

AF:

0.904

Gnomad OTH

AF:

0.804

GnomAD2 exomes

AF:

0.870

AC:

217090

AN:

249568

AF XY:

0.880

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.859

Gnomad ASJ exome

AF:

0.901

Gnomad EAS exome

AF:

0.910

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.904

Gnomad OTH exome

AF:

0.888

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.892

AC:

1303149

AN:

1461378

Hom.:

585879

Cov.:

AF XY:

0.894

AC XY:

650240

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.398

AC:

13321

AN:

33476

American (AMR)

AF:

0.856

AC:

38258

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.903

AC:

23582

AN:

26126

East Asian (EAS)

AF:

0.894

AC:

35496

AN:

39690

South Asian (SAS)

AF:

0.925

AC:

79779

AN:

86252

European-Finnish (FIN)

AF:

0.919

AC:

48752

AN:

53052

Middle Eastern (MID)

AF:

0.887

AC:

5116

AN:

5766

European-Non Finnish (NFE)

AF:

0.905

AC:

1006148

AN:

1111942

Other (OTH)

AF:

0.873

AC:

52697

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

8732

17464

26197

34929

43661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21364

42728

64092

85456

106820

<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:

0.766

AC:

116575

AN:

152194

Hom.:

48317

Cov.:

AF XY:

0.773

AC XY:

57525

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.416

AC:

17275

AN:

41498

American (AMR)

AF:

0.857

AC:

13110

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

3106

AN:

3472

East Asian (EAS)

AF:

0.909

AC:

4685

AN:

5154

South Asian (SAS)

AF:

0.930

AC:

4490

AN:

4830

European-Finnish (FIN)

AF:

0.911

AC:

9677

AN:

10626

Middle Eastern (MID)

AF:

0.860

AC:

251

AN:

292

European-Non Finnish (NFE)

AF:

0.904

AC:

61470

AN:

67994

Other (OTH)

AF:

0.801

AC:

1692

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1051

2101

3152

4202

5253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

830

1660

2490

3320

4150

<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:

0.863

Hom.:

107138

Bravo

AF:

0.747

TwinsUK

AF:

0.909

AC:

3372

ALSPAC

AF:

0.907

AC:

3495

ESP6500AA

AF:

0.430

AC:

1892

ESP6500EA

AF:

0.903

AC:

7763

ExAC

AF:

0.860

AC:

104343

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

EpiCase

AF:

0.908

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

2.5

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Benign

0.078

Sift

Benign

0.097

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.031

.;B

Vest4

0.064

MPC

0.40

ClinPred

0.038

GERP RS

1.9

Varity_R

0.10

gMVP

0.63

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over