Genetic Variant DUOX2:p.Arg376Gly (chr15-45109895-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_001363711.2(DUOX2):c.1126C>G(p.Arg376Gly) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DUOX2
NM_001363711.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

Publications

23 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-45109895-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363711.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.1126C>G	p.Arg376Gly	missense	Exon 10 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.1126C>G	p.Arg376Gly	missense	Exon 10 of 34	NP_054799.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.1126C>G	p.Arg376Gly	missense	Exon 10 of 34	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1	TSL:1	c.1126C>G	p.Arg376Gly	missense	Exon 10 of 34	ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1	TSL:5	n.1457C>G		non_coding_transcript_exon	Exon 7 of 17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.059

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.086

MetaRNN

Pathogenic

0.82

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.4

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.39

Sift

Benign

0.042

Sift4G

Uncertain

0.053

Polyphen

0.95

Vest4

0.80

MutPred

0.67

Loss of MoRF binding (P = 0.0414)

MVP

0.87

MPC

0.42

ClinPred

0.99

GERP RS

5.7

Varity_R

0.66

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over