rs530719719

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting

The NM_001363711.2(DUOX2):c.2895_2898delGTTC(p.Phe966SerfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.00284 in 1,613,794 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S965S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 12 hom. )

Consequence

DUOX2
NM_001363711.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 4.91

Publications

18 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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: Pathogenic. The variant received 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 15-45101227-TGAAC-T is Pathogenic according to our data. Variant chr15-45101227-TGAAC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	NP_054799.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1	TSL:1	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1	TSL:5	n.5144_5147delGTTC		non_coding_transcript_exon	Exon 15 of 17

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

397

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000845

Gnomad AMI

AF:

0.00330

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00979

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00294

AC:

736

AN:

250634

AF XY:

0.00288

show subpopulations

Gnomad AFR exome

AF:

0.000621

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0117

Gnomad NFE exome

AF:

0.00291

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00286

AC:

4183

AN:

1461500

Hom.:

AF XY:

0.00287

AC XY:

2087

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33476

American (AMR)

AF:

0.00179

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00265

AC:

228

AN:

86180

European-Finnish (FIN)

AF:

0.0112

AC:

598

AN:

53290

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00279

AC:

3100

AN:

1111900

Other (OTH)

AF:

0.00268

AC:

162

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

228

456

685

913

1141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00261

AC:

398

AN:

152294

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41546

American (AMR)

AF:

0.00203

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00228

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00979

AC:

104

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000667

Hom.:

Bravo

AF:

0.00207

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00273

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Thyroid dyshormonogenesis 6 (12)

not provided (5)

Congenital hypothyroidism (1)

DUOX2-related disorder (1)

Familial thyroid dyshormonogenesis (1)

Familial thyroid dyshormonogenesis;C4749351:Genetic transient congenital hypothyroidism (1)

Inborn genetic diseases (1)

Nongoitrous Euthyroid Hyperthyrotropinemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.9

Mutation Taster

=12/188

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: -22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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