15-45100816-G-C

Variant names:

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.2944C>G(p.Pro982Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,613,610 control chromosomes in the GnomAD database, including 2,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P982L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.047 ( 218 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2302 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.510

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: 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002041787).

BP6

Variant 15-45100816-G-C is Benign according to our data. Variant chr15-45100816-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

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.2944C>G	p.Pro982Ala	missense	Exon 23 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.2944C>G	p.Pro982Ala	missense	Exon 23 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.2944C>G	p.Pro982Ala	missense	Exon 23 of 34	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1	TSL:1	c.2944C>G	p.Pro982Ala	missense	Exon 23 of 34	ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1	TSL:5	n.5559C>G		non_coding_transcript_exon	Exon 15 of 17

Frequencies

GnomAD3 genomes

AF:

0.0475

AC:

7220

AN:

152084

Hom.:

217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0305

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0565

Gnomad ASJ

AF:

0.0646

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0353

Gnomad FIN

AF:

0.0644

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.0564

Gnomad OTH

AF:

0.0478

GnomAD2 exomes

AF:

0.0500

AC:

12442

AN:

248956

AF XY:

0.0504

show subpopulations

Gnomad AFR exome

AF:

0.0297

Gnomad AMR exome

AF:

0.0697

Gnomad ASJ exome

AF:

0.0654

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0587

Gnomad NFE exome

AF:

0.0552

Gnomad OTH exome

AF:

0.0540

GnomAD4 exome

AF:

0.0533

AC:

77936

AN:

1461408

Hom.:

2302

Cov.:

AF XY:

0.0532

AC XY:

38674

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0305

AC:

1021

AN:

33468

American (AMR)

AF:

0.0709

AC:

3171

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0634

AC:

1657

AN:

26132

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0377

AC:

3252

AN:

86248

European-Finnish (FIN)

AF:

0.0570

AC:

3043

AN:

53402

Middle Eastern (MID)

AF:

0.0527

AC:

304

AN:

5766

European-Non Finnish (NFE)

AF:

0.0562

AC:

62477

AN:

1111592

Other (OTH)

AF:

0.0497

AC:

3000

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

4034

8068

12102

16136

20170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2330

4660

6990

9320

11650

<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:

0.0475

AC:

7227

AN:

152202

Hom.:

218

Cov.:

AF XY:

0.0473

AC XY:

3517

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0305

AC:

1267

AN:

41530

American (AMR)

AF:

0.0568

AC:

868

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0646

AC:

224

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5164

South Asian (SAS)

AF:

0.0353

AC:

170

AN:

4814

European-Finnish (FIN)

AF:

0.0644

AC:

683

AN:

10610

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0565

AC:

3839

AN:

68006

Other (OTH)

AF:

0.0473

AC:

100

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

346

693

1039

1386

1732

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<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:

0.0420

Hom.:

Bravo

AF:

0.0465

TwinsUK

AF:

0.0526

AC:

195

ALSPAC

AF:

0.0550

AC:

212

ESP6500AA

AF:

0.0243

AC:

107

ESP6500EA

AF:

0.0409

AC:

352

ExAC

AF:

0.0479

AC:

5812

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0540

EpiControl

AF:

0.0506

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (1)

Thyroid dyshormonogenesis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.043

(source)

DANN

Benign

0.096

DEOGEN2

Benign

0.019

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.51

PrimateAI

Benign

0.25

PROVEAN

Benign

0.11

REVEL

Benign

0.029

Sift

Benign

0.33

Sift4G

Benign

0.90

Polyphen

0.0

Vest4

0.10

MPC

0.058

ClinPred

0.00071

GERP RS

-0.60

Varity_R

0.024

gMVP

0.48

Mutation Taster

=78/22

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

Computational scores

Splicing

Publications

Other links and lift over