rs73406334

Variant names:

• chr15-45105691-C-T
• rs73406334
• NM_001363711.2:c.2286G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001363711.2(DUOX2):​c.2286G>A​(p.Gln762Gln) 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:5
• Conservation: PhyloP100: 1.78
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 260320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2286G>A	p.Gln762Gln	synonymous	Exon 18 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.2286G>A	p.Gln762Gln	synonymous	Exon 18 of 34	NP_054799.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.2286G>A	p.Gln762Gln	synonymous	Exon 18 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.2286G>A	p.Gln762Gln	synonymous	Exon 18 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.4017G>A		non_coding_transcript_exon	Exon 12 of 17

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

GnomAD2 exomes AF: 0.0675 AC: 16969 AN: 251466 AF XY: 0.0676

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 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

African (AFR) AF: 0.0910 AC: 3047 AN: 33480

American (AMR) AF: 0.0796 AC: 3560 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 2040 AN: 26136

East Asian (EAS) AF: 0.0386 AC: 1531 AN: 39700

South Asian (SAS) AF: 0.0554 AC: 4779 AN: 86258

European-Finnish (FIN) AF: 0.0630 AC: 3364 AN: 53414

Middle Eastern (MID) AF: 0.0725 AC: 418 AN: 5768

European-Non Finnish (NFE) AF: 0.0730 AC: 81169 AN: 1112000

Other (OTH) AF: 0.0706 AC: 4263 AN: 60396

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

African (AFR) AF: 0.0883 AC: 3670 AN: 41562

American (AMR) AF: 0.0720 AC: 1102 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0830 AC: 288 AN: 3470

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5186

South Asian (SAS) AF: 0.0520 AC: 251 AN: 4824

European-Finnish (FIN) AF: 0.0695 AC: 738 AN: 10612

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0725 AC: 4934 AN: 68024

Other (OTH) AF: 0.0672 AC: 142 AN: 2112

Alfa AF: 0.0741 Hom.: 366

Bravo AF: 0.0750

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0705

EpiControl AF: 0.0654

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Thyroid dyshormonogenesis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.7
DANN	Benign	0.75
PhyloP100		1.8
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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