dbSNP rs113400262: DUOX2:p.Arg701Leu (chr15-45106171-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001363711.2(DUOX2):c.2102G>T(p.Arg701Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R701Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.38

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.110675395).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.2102G>T	p.Arg701Leu	missense_variant	Exon 17 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.2102G>T	p.Arg701Leu	missense_variant	Exon 17 of 34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.2102G>T	p.Arg701Leu	missense_variant	Exon 17 of 34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.2102G>T	p.Arg701Leu	missense_variant	Exon 17 of 34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.3833G>T		non_coding_transcript_exon_variant	Exon 11 of 17	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 701 of the DUOX2 protein (p.Arg701Leu). This variant is present in population databases (rs113400262, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DUOX2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DUOX2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-2.9

D;.

REVEL

Benign

0.034

Sift

Benign

0.33

T;.

Sift4G

Benign

0.64

T;T

Polyphen

0.0070

.;B

Vest4

0.17

MutPred

0.51

Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);

MVP

0.75

MPC

0.071

ClinPred

0.070

GERP RS

-2.0

Varity_R

0.080

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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