rs73406330

Positions:

• chr15-45105633-G-A
• chr15-45105633-G-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.2334+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0885 in 1,613,860 control chromosomes in the GnomAD database, including 9,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2930 hom., cov: 32)
  • Exomes 𝑓: 0.082 (6613 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.53

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=-0.78).
• BP6: Variant 15-45105633-G-A is Benign according to our data. Variant chr15-45105633-G-A is described in ClinVar as [Benign]. Clinvar id is 260321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45105633-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.2334+10C>T		intron_variant		ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.2334+10C>T		intron_variant			NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.2334+10C>T		intron_variant		1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1	c.2334+10C>T		intron_variant		1		ENSP00000475084	A1
DUOX2	ENST00000558383.1	n.4065+10C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22991 AN: 152010 Hom.: 2915 Cov.: 32

Gnomad AFR AF: 0.344

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0850

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0759

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0748

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.0946 AC: 23745 AN: 250904 Hom.: 1850 AF XY: 0.0886 AC XY: 12024 AN XY: 135658

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.0813

Gnomad EAS exome AF: 0.0503

Gnomad SAS exome AF: 0.0601

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0736

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.0820 AC: 119845 AN: 1461732 Hom.: 6613 Cov.: 33 AF XY: 0.0805 AC XY: 58507 AN XY: 727182

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.0791

Gnomad4 EAS exome AF: 0.0554

Gnomad4 SAS exome AF: 0.0595

Gnomad4 FIN exome AF: 0.0680

Gnomad4 NFE exome AF: 0.0748

Gnomad4 OTH exome AF: 0.0940

GnomAD4 genome AF: 0.152 AC: 23056 AN: 152128 Hom.: 2930 Cov.: 32 AF XY: 0.148 AC XY: 11038 AN XY: 74406

Gnomad4 AFR AF: 0.344

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0850

Gnomad4 EAS AF: 0.0512

Gnomad4 SAS AF: 0.0562

Gnomad4 FIN AF: 0.0759

Gnomad4 NFE AF: 0.0749

Gnomad4 OTH AF: 0.131

Alfa AF: 0.0853 Hom.: 248

Bravo AF: 0.163

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

Significance: 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Thyroid dyshormonogenesis 6 Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.63
DANN	Benign	0.74

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: rs73406330; hg19: chr15-45397831;