rs57659670

Positions:

chr15-45106240-T-C

Variant summary

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

The NM_001363711.2(DUOX2):c.2033A>G(p.His678Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,613,922 control chromosomes in the GnomAD database, including 10,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 3586 hom., cov: 32)

Exomes 𝑓: 0.083 ( 7212 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0520

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=0.0027880967).

BP6

Variant 15-45106240-T-C is Benign according to our data. Variant chr15-45106240-T-C is described in ClinVar as [Benign]. Clinvar id is 260317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45106240-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 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.2033A>G	p.His678Arg	missense_variant	17/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 linkuse as main transcript	c.2033A>G	p.His678Arg	missense_variant	17/34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 linkuse as main transcript	c.2033A>G	p.His678Arg	missense_variant	17/34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 linkuse as main transcript	c.2033A>G	p.His678Arg	missense_variant	17/34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 linkuse as main transcript	n.3764A>G		non_coding_transcript_exon_variant	11/17	5

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24856

AN:

151996

Hom.:

3571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.386

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.116

Gnomad ASJ

AF:

0.0853

Gnomad EAS

AF:

0.0513

Gnomad SAS

AF:

0.0560

Gnomad FIN

AF:

0.0762

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.0751

Gnomad OTH

AF:

0.138

GnomAD3 exomes

AF:

0.0977

AC:

24527

AN:

251162

Hom.:

2114

AF XY:

0.0907

AC XY:

12319

AN XY:

135772

show subpopulations

Gnomad AFR exome

AF:

0.390

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0813

Gnomad EAS exome

AF:

0.0502

Gnomad SAS exome

AF:

0.0607

Gnomad FIN exome

AF:

0.0686

Gnomad NFE exome

AF:

0.0738

Gnomad OTH exome

AF:

0.0880

GnomAD4 exome

AF:

0.0833

AC:

121760

AN:

1461810

Hom.:

7212

Cov.:

AF XY:

0.0816

AC XY:

59325

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.401

Gnomad4 AMR exome

AF:

0.122

Gnomad4 ASJ exome

AF:

0.0791

Gnomad4 EAS exome

AF:

0.0554

Gnomad4 SAS exome

AF:

0.0600

Gnomad4 FIN exome

AF:

0.0682

Gnomad4 NFE exome

AF:

0.0750

Gnomad4 OTH exome

AF:

0.0966

GnomAD4 genome

AF:

0.164

AC:

24920

AN:

152112

Hom.:

3586

Cov.:

AF XY:

0.160

AC XY:

11894

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.386

Gnomad4 AMR

AF:

0.117

Gnomad4 ASJ

AF:

0.0853

Gnomad4 EAS

AF:

0.0512

Gnomad4 SAS

AF:

0.0564

Gnomad4 FIN

AF:

0.0762

Gnomad4 NFE

AF:

0.0751

Gnomad4 OTH

AF:

0.141

Alfa

AF:

0.0899

Hom.:

1585

Bravo

AF:

0.176

TwinsUK

AF:

0.0701

AC:

260

ALSPAC

AF:

0.0763

AC:

294

ESP6500AA

AF:

0.388

AC:

1705

ESP6500EA

AF:

0.0753

AC:

647

ExAC

AF:

0.102

AC:

12389

Asia WGS

AF:

0.115

AC:

399

AN:

3478

EpiCase

AF:

0.0736

EpiControl

AF:

0.0684

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 25248169, 24423310, 21900383, 20981092, 25616291, 18765513, 27884173, 23239635, 25263060, 26565538, 21565790, 28666341) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Thyroid dyshormonogenesis 6

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.12

DANN

Benign

0.24

DEOGEN2

Benign

0.0050

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0061

LIST_S2

Benign

0.022

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-1.3

.;N

PrimateAI

Benign

0.21

PROVEAN

Benign

2.1

N;.

REVEL

Benign

0.096

Sift

Benign

1.0

T;.

Sift4G

Benign

0.91

T;T

Polyphen

0.0

.;B

Vest4

0.050

MPC

0.069

ClinPred

0.0029

GERP RS

-0.37

Varity_R

0.023

gMVP

0.10

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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