rs73406337

chr15-45106116-G-Achr15-45106116-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.2148+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,613,674 control chromosomes in the GnomAD database, including 4,400 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 (451 hom., cov: 32)
  • Exomes 𝑓: 0.071 (3949 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.77

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=-0.85).
• BP6: Variant 15-45106116-G-A is Benign according to our data. Variant chr15-45106116-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45106116-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.2148+9C>T		intron_variant		ENST00000389039.11
DUOX2	NM_014080.5	c.2148+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.2148+9C>T		intron_variant		1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.2148+9C>T		intron_variant		1		A1
DUOX2	ENST00000558383.1	n.3879+9C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11300 AN: 152154 Hom.: 450 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0718

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0725

Gnomad OTH AF: 0.0640

GnomAD3 exomes AF: 0.0673 AC: 16896 AN: 250964 Hom.: 670 AF XY: 0.0674 AC XY: 9140 AN XY: 135678

Gnomad AFR exome AF: 0.0873

Gnomad AMR exome AF: 0.0772

Gnomad ASJ exome AF: 0.0804

Gnomad EAS exome AF: 0.0250

Gnomad SAS exome AF: 0.0554

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.0709

Gnomad OTH exome AF: 0.0706

GnomAD4 exome AF: 0.0712 AC: 103986 AN: 1461402 Hom.: 3949 Cov.: 33 AF XY: 0.0708 AC XY: 51489 AN XY: 727054

Gnomad4 AFR exome AF: 0.0910

Gnomad4 AMR exome AF: 0.0794

Gnomad4 ASJ exome AF: 0.0780

Gnomad4 EAS exome AF: 0.0386

Gnomad4 SAS exome AF: 0.0551

Gnomad4 FIN exome AF: 0.0629

Gnomad4 NFE exome AF: 0.0729

Gnomad4 OTH exome AF: 0.0705

GnomAD4 genome AF: 0.0744 AC: 11322 AN: 152272 Hom.: 451 Cov.: 32 AF XY: 0.0733 AC XY: 5461 AN XY: 74464

Gnomad4 AFR AF: 0.0882

Gnomad4 AMR AF: 0.0720

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.0245

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0694

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.0671

Alfa AF: 0.0665 Hom.: 200

Bravo AF: 0.0750

Asia WGS AF: 0.0530 AC: 185 AN: 3478

EpiCase AF: 0.0707

EpiControl AF: 0.0653

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	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 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	-0.85
Cadd	Benign	0.031
Dann	Benign	0.55

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: rs73406337; hg19: chr15-45398314; COSMIC: COSV66534169; COSMIC: COSV66534169;