15-45110685-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001363711.2(DUOX2):c.908C>G(p.Pro303Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,612,426 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 32)

Exomes 𝑓: 0.014 ( 165 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.19

Publications

15 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012326807).

BP6

Variant 15-45110685-G-C is Benign according to our data. Variant chr15-45110685-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260328.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1616/152278) while in subpopulation NFE AF = 0.0165 (1121/68026). AF 95% confidence interval is 0.0157. There are 21 homozygotes in GnomAd4. There are 680 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363711.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.908C>G	p.Pro303Arg	missense	Exon 8 of 34	NP_001350640.1
	DUOX2	NM_014080.5		c.908C>G	p.Pro303Arg	missense	Exon 8 of 34	NP_054799.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.908C>G	p.Pro303Arg	missense	Exon 8 of 34	ENSP00000373691.7
DUOX2	ENST00000603300.1	TSL:1	c.908C>G	p.Pro303Arg	missense	Exon 8 of 34	ENSP00000475084.1
DUOX2	ENST00000558383.1	TSL:5	n.1239C>G		non_coding_transcript_exon	Exon 5 of 17

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1615

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0232

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0109

AC:

2740

AN:

251084

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00741

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00509

Gnomad NFE exome

AF:

0.0173

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0139

AC:

20333

AN:

1460148

Hom.:

165

Cov.:

AF XY:

0.0137

AC XY:

9930

AN XY:

726400

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33420

American (AMR)

AF:

0.00819

AC:

366

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0243

AC:

634

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86188

European-Finnish (FIN)

AF:

0.00537

AC:

287

AN:

53418

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

4442

European-Non Finnish (NFE)

AF:

0.0162

AC:

17971

AN:

1111896

Other (OTH)

AF:

0.0125

AC:

755

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

1292

2584

3875

5167

6459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.0106

AC:

1616

AN:

152278

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

680

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00286

AC:

119

AN:

41560

American (AMR)

AF:

0.0111

AC:

169

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00249

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00574

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1121

AN:

68026

Other (OTH)

AF:

0.0133

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0166

Hom.:

Bravo

AF:

0.0115

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0106

AC:

1292

EpiCase

AF:

0.0192

EpiControl

AF:

0.0186

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31030636, 27373512)

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Thyroid dyshormonogenesis 6

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.012

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.8

PhyloP100

7.2

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-8.2

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.36

MPC

0.38

ClinPred

0.064

GERP RS

5.6

Varity_R

0.92

gMVP

0.81

Mutation Taster

=68/32

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