rs269868

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001363711.2(DUOX2):c.3200C>T(p.Ser1067Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,613,952 control chromosomes in the GnomAD database, including 655,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.73 ( 47658 hom., cov: 32)

Exomes 𝑓: 0.91 ( 607648 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.628715E-7).

BP6

Variant 15-45099877-G-A is Benign according to our data. Variant chr15-45099877-G-A is described in ClinVar as [Benign]. Clinvar id is 260323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45099877-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2 linkuse as main transcript	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 linkuse as main transcript	c.3200C>T	p.Ser1067Leu	missense_variant	25/34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DUOX2	ENST00000389039.11 linkuse as main transcript	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1 linkuse as main transcript	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	1		ENSP00000475084	A1
DUOX2	ENST00000558383.1 linkuse as main transcript	n.5972C>T		non_coding_transcript_exon_variant	16/17	5
DUOX2	ENST00000560797.1 linkuse as main transcript	n.380C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111516

AN:

151994

Hom.:

47671

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.954

Gnomad AMR

AF:

0.855

Gnomad ASJ

AF:

0.924

Gnomad EAS

AF:

0.945

Gnomad SAS

AF:

0.944

Gnomad FIN

AF:

0.921

Gnomad MID

AF:

0.873

Gnomad NFE

AF:

0.922

Gnomad OTH

AF:

0.790

GnomAD3 exomes

AF:

0.875

AC:

219774

AN:

251092

Hom.:

99867

AF XY:

0.890

AC XY:

120799

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.242

Gnomad AMR exome

AF:

0.865

Gnomad ASJ exome

AF:

0.928

Gnomad EAS exome

AF:

0.947

Gnomad SAS exome

AF:

0.939

Gnomad FIN exome

AF:

0.929

Gnomad NFE exome

AF:

0.924

Gnomad OTH exome

AF:

0.901

GnomAD4 exome

AF:

0.905

AC:

1323562

AN:

1461838

Hom.:

607648

Cov.:

AF XY:

0.909

AC XY:

660817

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.236

Gnomad4 AMR exome

AF:

0.862

Gnomad4 ASJ exome

AF:

0.930

Gnomad4 EAS exome

AF:

0.943

Gnomad4 SAS exome

AF:

0.940

Gnomad4 FIN exome

AF:

0.929

Gnomad4 NFE exome

AF:

0.923

Gnomad4 OTH exome

AF:

0.883

GnomAD4 genome

AF:

0.733

AC:

111506

AN:

152114

Hom.:

47658

Cov.:

AF XY:

0.742

AC XY:

55203

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.254

Gnomad4 AMR

AF:

0.855

Gnomad4 ASJ

AF:

0.924

Gnomad4 EAS

AF:

0.945

Gnomad4 SAS

AF:

0.943

Gnomad4 FIN

AF:

0.921

Gnomad4 NFE

AF:

0.922

Gnomad4 OTH

AF:

0.787

Alfa

AF:

0.889

Hom.:

136966

Bravo

AF:

0.707

TwinsUK

AF:

0.927

AC:

3436

ALSPAC

AF:

0.919

AC:

3542

ESP6500AA

AF:

0.269

AC:

1182

ESP6500EA

AF:

0.925

AC:

7948

ExAC

AF:

0.864

AC:

104920

Asia WGS

AF:

0.854

AC:

2969

AN:

3478

EpiCase

AF:

0.924

EpiControl

AF:

0.931

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;T

MetaRNN

Benign

9.6e-7

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.4

.;M

MutationTaster

Benign

1.5e-7

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.30

Sift

Benign

0.043

D;.

Sift4G

Benign

0.075

T;T

Polyphen

0.025

.;B

Vest4

0.23

MPC

0.057

ClinPred

0.045

GERP RS

5.6

Varity_R

0.31

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over