rs2001616

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.413C>T(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,194 control chromosomes in the GnomAD database, including 48,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 48317 hom., cov: 33)

Exomes 𝑓: 0.89 ( 585879 hom. )

Failed GnomAD Quality Control

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.47

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:

DUOX2 (HGNC:):

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=1.5484195E-6).

BP6

Variant 15-45111868-G-A is Benign according to our data. Variant chr15-45111868-G-A is described in ClinVar as [Benign]. Clinvar id is 260326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45111868-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.907 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.413C>T	p.Pro138Leu	missense_variant	5/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	5/34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	5/34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 linkuse as main transcript	c.413C>T	p.Pro138Leu	missense_variant	5/34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 linkuse as main transcript	n.456C>T		non_coding_transcript_exon_variant	4/17	5

Frequencies

GnomAD3 genomes

AF:

0.766

AC:

116562

AN:

152076

Hom.:

48324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.417

Gnomad AMI

AF:

0.898

Gnomad AMR

AF:

0.857

Gnomad ASJ

AF:

0.895

Gnomad EAS

AF:

0.909

Gnomad SAS

AF:

0.930

Gnomad FIN

AF:

0.911

Gnomad MID

AF:

0.863

Gnomad NFE

AF:

0.904

Gnomad OTH

AF:

0.804

GnomAD3 exomes

AF:

0.870

AC:

217090

AN:

249568

Hom.:

96466

AF XY:

0.880

AC XY:

119118

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.859

Gnomad ASJ exome

AF:

0.901

Gnomad EAS exome

AF:

0.910

Gnomad SAS exome

AF:

0.924

Gnomad FIN exome

AF:

0.919

Gnomad NFE exome

AF:

0.904

Gnomad OTH exome

AF:

0.888

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.892

AC:

1303149

AN:

1461378

Hom.:

585879

Cov.:

AF XY:

0.894

AC XY:

650240

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.398

Gnomad4 AMR exome

AF:

0.856

Gnomad4 ASJ exome

AF:

0.903

Gnomad4 EAS exome

AF:

0.894

Gnomad4 SAS exome

AF:

0.925

Gnomad4 FIN exome

AF:

0.919

Gnomad4 NFE exome

AF:

0.905

Gnomad4 OTH exome

AF:

0.873

GnomAD4 genome

AF:

0.766

AC:

116575

AN:

152194

Hom.:

48317

Cov.:

AF XY:

0.773

AC XY:

57525

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.416

Gnomad4 AMR

AF:

0.857

Gnomad4 ASJ

AF:

0.895

Gnomad4 EAS

AF:

0.909

Gnomad4 SAS

AF:

0.930

Gnomad4 FIN

AF:

0.911

Gnomad4 NFE

AF:

0.904

Gnomad4 OTH

AF:

0.801

Alfa

AF:

0.843

Hom.:

34763

Bravo

AF:

0.747

TwinsUK

AF:

0.909

AC:

3372

ALSPAC

AF:

0.907

AC:

3495

ESP6500AA

AF:

0.430

AC:

1892

ESP6500EA

AF:

0.903

AC:

7763

ExAC

AF:

0.860

AC:

104343

Asia WGS

AF:

0.838

AC:

2915

AN:

3478

EpiCase

AF:

0.908

EpiControl

AF:

0.910

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

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

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.8

D;.

REVEL

Benign

0.078

Sift

Benign

0.097

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.031

.;B

Vest4

0.064

MPC

0.40

ClinPred

0.038

GERP RS

1.9

Varity_R

0.10

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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