Genetic Variant DUOX2:p.Gly200Arg (chr15-45111501-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001363711.2(DUOX2):c.598G>C(p.Gly200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 6
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DUOX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31631523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.598G>C	p.Gly200Arg	missense_variant	Exon 6 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.598G>C	p.Gly200Arg	missense_variant	Exon 6 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.598G>C	p.Gly200Arg	missense_variant	Exon 6 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.598G>C	p.Gly200Arg	missense_variant	Exon 6 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.823G>C		non_coding_transcript_exon_variant	Exon 4 of 17	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399544

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31328

American (AMR)

AF:

0.00

AC:

AN:

36272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

36130

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4070

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083100

Other (OTH)

AF:

0.00

AC:

AN:

57878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.32

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.3

.;M

PhyloP100

1.1

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.21

Sift

Benign

0.16

T;.

Sift4G

Benign

0.24

T;T

Polyphen

0.049

.;B

Vest4

0.33

MutPred

0.65

Gain of solvent accessibility (P = 0.0097);Gain of solvent accessibility (P = 0.0097);

MVP

0.61

MPC

0.59

ClinPred

0.57

GERP RS

3.2

Varity_R

0.18

gMVP

0.46

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over