rs138353181

Positions:

chr15-45105795-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

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:

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=0.0038830042).

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
DUOX2	ENST00000389039.11 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/34	1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1 linkuse as main transcript	c.2182G>A	p.Ala728Thr	missense_variant	18/34	1		ENSP00000475084	A1
DUOX2	ENST00000558383.1 linkuse as main transcript	n.3913G>A		non_coding_transcript_exon_variant	12/17	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

GnomAD3 exomes

AF:

0.00814

AC:

2046

AN:

251212

Hom.:

AF XY:

0.00764

AC XY:

1038

AN XY:

135818

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 SAS exome

AF:

0.00340

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

Gnomad4 AMR exome

AF:

0.0159

Gnomad4 ASJ exome

AF:

0.00708

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00310

Gnomad4 FIN exome

AF:

0.00416

Gnomad4 NFE exome

AF:

0.00847

Gnomad4 OTH exome

AF:

0.00831

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

Gnomad4 AMR

AF:

0.0218

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00414

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00889

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.00819

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

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DUOX2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 23, 2015	- -

Thyroid dyshormonogenesis 6

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Likely benign, criteria provided, single submitter

research

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

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

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

MutationTaster

Benign

1.0

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

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