15-45106552-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001363711.2(DUOX2):c.1921G>A(p.Glu641Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,180 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 21 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 0.0540

Publications

10 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004345).

BP6

Variant 15-45106552-C-T is Benign according to our data. Variant chr15-45106552-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 418789. Variant chr15-45106552-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 418789. Variant chr15-45106552-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 418789. Variant chr15-45106552-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 418789.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.1921G>A	p.Glu641Lys	missense_variant	Exon 16 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.1921G>A	p.Glu641Lys	missense_variant	Exon 16 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.1921G>A	p.Glu641Lys	missense_variant	Exon 16 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.1921G>A	p.Glu641Lys	missense_variant	Exon 16 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.3652G>A		non_coding_transcript_exon_variant	Exon 10 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

502

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00316

AC:

794

AN:

251494

AF XY:

0.00297

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00273

Gnomad NFE exome

AF:

0.00512

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00532

AC:

7782

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

3780

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33480

American (AMR)

AF:

0.00197

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00147

AC:

127

AN:

86256

European-Finnish (FIN)

AF:

0.00303

AC:

162

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00638

AC:

7094

AN:

1112004

Other (OTH)

AF:

0.00424

AC:

256

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

460

920

1381

1841

2301

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.00330

AC:

502

AN:

152302

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

212

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41558

American (AMR)

AF:

0.00216

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00559

AC:

380

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

109

136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00452

Hom.:

Bravo

AF:

0.00319

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00570

AC:

ExAC

AF:

0.00292

AC:

355

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00371

EpiControl

AF:

0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 19, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DUOX2: BP4, BS2 -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Thyroid dyshormonogenesis 6

Uncertain:2

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. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DUOX2 c.1921G>A (p.Glu641Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251494 control chromosomes in the gnomAD database, including 2 homozygotes suggesting a benign role for this variant. c.1921G>A has been reported in the literature in an individual affected with congenital hypothyroidism with a non-informative genotype and the authors classified the variant as benign (example: de Filippis_2017 and Gentilini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Thyroid Dyshormonogenesis 6. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 08, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2; BP4; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and is predicted to be tolerated by multiple functional prediction tools. -

DUOX2-related disorder

Uncertain:1

Dec 05, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DUOX2 c.1921G>A variant is predicted to result in the amino acid substitution p.Glu641Lys. This patient is heterozygous in the DUOX2 gene for a sequence variant designated c.1921G>A, which is predicted to result in the amino acid substitution p.Glu641Lys. This variant has been reported in an individual with a thyroid anomaly who also presented with cleft palate and an atrial septal defect, however an additional variant in a different gene was also reported (CH83, Supplemental Table 3, de Filippis et al. 2017. PubMed ID: 28444304). This variant was identified in multiple individuals participating in a wellness-program and was deemed a variant of unknown physiologic significance (Supplemental table 1, Grasberger et al. 2021. PubMed ID: 33651715). This variant is reported at a subpopulation frequency of ~0.50% (including 2 homozygotes) in a database of individuals of unknown phenotype, which is high for a variant considered to be pathogenic for an autosomal recessive disorder (https://gnomad.broadinstitute.org/variant/15-45398750-C-T). This variant has conflicting interpretations regarding pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/418789/). While we suspect that this variant is benign, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0043

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

.;M

PhyloP100

0.054

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.85

N;.

REVEL

Benign

0.038

Sift

Benign

0.40

T;.

Sift4G

Benign

0.44

T;T

Polyphen

0.0020

.;B

Vest4

0.28

MVP

0.84

MPC

0.065

ClinPred

0.0050

GERP RS

2.2

Varity_R

0.053

gMVP

0.29

Mutation Taster

=98/2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over