rs73406334

chr15-45105691-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001363711.2(DUOX2):c.2286G>A(p.Gln762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 1,614,176 control chromosomes in the GnomAD database, including 4,412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (453 hom., cov: 32)
  • Exomes 𝑓: 0.071 (3959 hom.)
• Consequence: DUOX2 NM_001363711.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 15-45105691-C-T is Benign according to our data. Variant chr15-45105691-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45105691-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.2286G>A	p.Gln762=	synonymous_variant	18/34	ENST00000389039.11
DUOX2	NM_014080.5	c.2286G>A	p.Gln762=	synonymous_variant	18/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.2286G>A	p.Gln762=	synonymous_variant	18/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.2286G>A	p.Gln762=	synonymous_variant	18/34	1		A1
DUOX2	ENST00000558383.1	n.4017G>A		non_coding_transcript_exon_variant	12/17	5

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11307 AN: 152182 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0830

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0725

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0675 AC: 16969 AN: 251466 Hom.: 682 AF XY: 0.0676 AC XY: 9182 AN XY: 135912

Gnomad AFR exome AF: 0.0872

Gnomad AMR exome AF: 0.0775

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.0251

Gnomad SAS exome AF: 0.0557

Gnomad FIN exome AF: 0.0638

Gnomad NFE exome AF: 0.0710

Gnomad OTH exome AF: 0.0708

GnomAD4 exome AF: 0.0713 AC: 104171 AN: 1461876 Hom.: 3959 Cov.: 33 AF XY: 0.0709 AC XY: 51560 AN XY: 727240

Gnomad4 AFR exome AF: 0.0910

Gnomad4 AMR exome AF: 0.0796

Gnomad4 ASJ exome AF: 0.0781

Gnomad4 EAS exome AF: 0.0386

Gnomad4 SAS exome AF: 0.0554

Gnomad4 FIN exome AF: 0.0630

Gnomad4 NFE exome AF: 0.0730

Gnomad4 OTH exome AF: 0.0706

GnomAD4 genome AF: 0.0744 AC: 11329 AN: 152300 Hom.: 453 Cov.: 32 AF XY: 0.0733 AC XY: 5456 AN XY: 74466

Gnomad4 AFR AF: 0.0883

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.0830

Gnomad4 EAS AF: 0.0249

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0695

Gnomad4 NFE AF: 0.0725

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0762 Hom.: 247

Bravo AF: 0.0750

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0705

EpiControl AF: 0.0654

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Thyroid dyshormonogenesis 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	8.7
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs73406334; hg19: chr15-45397889; COSMIC: COSV66534165; COSMIC: COSV66534165;