chr15-45105795-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001363711.2(DUOX2):c.2182G>A(p.Ala728Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00776 in 1,614,188 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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. A728D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 62 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.0710

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:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0038830042).

BP6

Variant 15-45105795-C-T is Benign according to our data. Variant chr15-45105795-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 235495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45105795-C-T is described in Lovd as [Likely_benign]. Variant chr15-45105795-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00721 (1098/152344) while in subpopulation AMR AF = 0.0218 (334/15310). AF 95% confidence interval is 0.0199. There are 10 homozygotes in GnomAd4. There are 576 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.2182G>A	p.Ala728Thr	missense_variant	Exon 18 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.3913G>A		non_coding_transcript_exon_variant	Exon 12 of 17	5

Frequencies

GnomAD3 genomes

AF:

0.00718

AC:

1093

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00889

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00814

AC:

2046

AN:

251212

AF XY:

0.00764

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.00834

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00268

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00782

AC:

11429

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00778

AC XY:

5659

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00137

AC:

AN:

33478

Gnomad4 AMR exome

AF:

0.0159

AC:

713

AN:

44724

Gnomad4 ASJ exome

AF:

0.00708

AC:

185

AN:

26136

Gnomad4 EAS exome

AF:

0.0000252

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00310

AC:

267

AN:

86258

Gnomad4 FIN exome

AF:

0.00416

AC:

222

AN:

53380

Gnomad4 NFE exome

AF:

0.00847

AC:

9423

AN:

1112004

Gnomad4 Remaining exome

AF:

0.00831

AC:

502

AN:

60396

Heterozygous variant carriers

728

1456

2184

2912

3640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.00721

AC:

1098

AN:

152344

Hom.:

Cov.:

AF XY:

0.00773

AC XY:

576

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00106

AC:

0.0010582

AN:

0.0010582

Gnomad4 AMR

AF:

0.0218

AC:

0.0218158

AN:

0.0218158

Gnomad4 ASJ

AF:

0.00605

AC:

0.00604839

AN:

0.00604839

Gnomad4 EAS

AF:

0.000578

AC:

0.000578035

AN:

0.000578035

Gnomad4 SAS

AF:

0.00414

AC:

0.0041425

AN:

0.0041425

Gnomad4 FIN

AF:

0.00386

AC:

0.00386137

AN:

0.00386137

Gnomad4 NFE

AF:

0.00889

AC:

0.00889366

AN:

0.00889366

Gnomad4 OTH

AF:

0.0128

AC:

0.012772

AN:

0.012772

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00871

Hom.:

Bravo

AF:

0.00893

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00791

AC:

ExAC

AF:

0.00760

AC:

923

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0115

EpiControl

AF:

0.0116

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 23, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DUOX2: BP4, BS1, BS2 -

Thyroid dyshormonogenesis 6

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Meckel syndrome, type 11

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ala728Thr variant in DUOX2 has been identified in an individual with congenital hypothyroidism (PMID: 21565790), and has been identified in >1% of Latino chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that the p.Ala728Thr variant may not impact protein function (PMID: 21565790). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive congenital hypothyroidism. -

DUOX2-related disorder

Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.16

DANN

Benign

0.90

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.23

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

.;L

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.95

N;.

REVEL

Benign

0.0090

Sift

Benign

0.37

T;.

Sift4G

Benign

0.56

T;T

Polyphen

0.0070

.;B

Vest4

0.038

MVP

0.59

MPC

0.057

ClinPred

0.00028

GERP RS

-3.5

Varity_R

0.029

gMVP

0.13

Mutation Taster

=98/2

polymorphism

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

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