rs76411432

Positions:

• chr15-45107335-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363711.2(DUOX2):​c.1693+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,548 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (122 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (90 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.262

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-45107335-C-T is Benign according to our data. Variant chr15-45107335-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 260316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45107335-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.1693+10G>A		intron_variant		ENST00000389039.11
DUOX2	NM_014080.5	c.1693+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.1693+10G>A		intron_variant		1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.1693+10G>A		intron_variant		1		A1
DUOX2	ENST00000558383.1	n.3424+10G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3291 AN: 152212 Hom.: 123 Cov.: 31

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.00625 AC: 1573 AN: 251494 Hom.: 53 AF XY: 0.00470 AC XY: 639 AN XY: 135922

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00788

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00234 AC: 3417 AN: 1461218 Hom.: 90 Cov.: 32 AF XY: 0.00207 AC XY: 1506 AN XY: 726996

Gnomad4 AFR exome AF: 0.0736

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00388

Gnomad4 SAS exome AF: 0.00107

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000137

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.0217 AC: 3298 AN: 152330 Hom.: 122 Cov.: 31 AF XY: 0.0206 AC XY: 1534 AN XY: 74496

Gnomad4 AFR AF: 0.0735

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00791

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0191 Hom.: 25

Bravo AF: 0.0245

Asia WGS AF: 0.00866 AC: 30 AN: 3478

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	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

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	-0.86
CADD	Benign	14
DANN	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs76411432; hg19: chr15-45399533;