15-45110685-G-C

Position:

chr15-45110685-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001363711.2(DUOX2):c.908C>G(p.Pro303Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0136 in 1,612,426 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 32)

Exomes 𝑓: 0.014 ( 165 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.19

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012326807).

BP6

Variant 15-45110685-G-C is Benign according to our data. Variant chr15-45110685-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260328.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr15-45110685-G-C is described in Lovd as [Likely_benign]. Variant chr15-45110685-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0106 (1616/152278) while in subpopulation NFE AF= 0.0165 (1121/68026). AF 95% confidence interval is 0.0157. There are 21 homozygotes in gnomad4. There are 680 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2 linkuse as main transcript	c.908C>G	p.Pro303Arg	missense_variant	8/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 linkuse as main transcript	c.908C>G	p.Pro303Arg	missense_variant	8/34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 linkuse as main transcript	c.908C>G	p.Pro303Arg	missense_variant	8/34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 linkuse as main transcript	c.908C>G	p.Pro303Arg	missense_variant	8/34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 linkuse as main transcript	n.1239C>G		non_coding_transcript_exon_variant	5/17	5

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1615

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.0232

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0134

GnomAD3 exomes

AF:

0.0109

AC:

2740

AN:

251084

Hom.:

AF XY:

0.0105

AC XY:

1430

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00741

Gnomad ASJ exome

AF:

0.0234

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00199

Gnomad FIN exome

AF:

0.00509

Gnomad NFE exome

AF:

0.0173

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.0139

AC:

20333

AN:

1460148

Hom.:

165

Cov.:

AF XY:

0.0137

AC XY:

9930

AN XY:

726400

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.00819

Gnomad4 ASJ exome

AF:

0.0243

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00211

Gnomad4 FIN exome

AF:

0.00537

Gnomad4 NFE exome

AF:

0.0162

Gnomad4 OTH exome

AF:

0.0125

GnomAD4 genome

AF:

0.0106

AC:

1616

AN:

152278

Hom.:

Cov.:

AF XY:

0.00913

AC XY:

680

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.0236

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00574

Gnomad4 NFE

AF:

0.0165

Gnomad4 OTH

AF:

0.0133

Alfa

AF:

0.0166

Hom.:

Bravo

AF:

0.0115

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0106

AC:

1292

EpiCase

AF:

0.0192

EpiControl

AF:

0.0186

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 31030636, 27373512) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Thyroid dyshormonogenesis 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D

MetaRNN

Benign

0.012

T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.8

.;H

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-8.2

D;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.36

MPC

0.38

ClinPred

0.064

GERP RS

5.6

Varity_R

0.92

gMVP

0.81

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