rs269868

chr15-45099877-G-Achr15-45099877-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.3200C>T(p.Ser1067Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,613,952 control chromosomes in the GnomAD database, including 655,306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (47658 hom., cov: 32)
  • Exomes 𝑓: 0.91 (607648 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.05

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 (MetaRNN=9.628715E-7).
• BP6: Variant 15-45099877-G-A is Benign according to our data. Variant chr15-45099877-G-A is described in ClinVar as [Benign]. Clinvar id is 260323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45099877-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	ENST00000389039.11
DUOX2	NM_014080.5	c.3200C>T	p.Ser1067Leu	missense_variant	25/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.3200C>T	p.Ser1067Leu	missense_variant	25/34	1		A1
DUOX2	ENST00000558383.1	n.5972C>T		non_coding_transcript_exon_variant	16/17	5
DUOX2	ENST00000560797.1	n.380C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111516 AN: 151994 Hom.: 47671 Cov.: 32

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.924

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.944

Gnomad FIN AF: 0.921

Gnomad MID AF: 0.873

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.790

GnomAD3 exomes AF: 0.875 AC: 219774 AN: 251092 Hom.: 99867 AF XY: 0.890 AC XY: 120799 AN XY: 135798

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.947

Gnomad SAS exome AF: 0.939

Gnomad FIN exome AF: 0.929

Gnomad NFE exome AF: 0.924

Gnomad OTH exome AF: 0.901

GnomAD4 exome AF: 0.905 AC: 1323562 AN: 1461838 Hom.: 607648 Cov.: 63 AF XY: 0.909 AC XY: 660817 AN XY: 727224

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.862

Gnomad4 ASJ exome AF: 0.930

Gnomad4 EAS exome AF: 0.943

Gnomad4 SAS exome AF: 0.940

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.883

GnomAD4 genome AF: 0.733 AC: 111506 AN: 152114 Hom.: 47658 Cov.: 32 AF XY: 0.742 AC XY: 55203 AN XY: 74352

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.855

Gnomad4 ASJ AF: 0.924

Gnomad4 EAS AF: 0.945

Gnomad4 SAS AF: 0.943

Gnomad4 FIN AF: 0.921

Gnomad4 NFE AF: 0.922

Gnomad4 OTH AF: 0.787

Alfa AF: 0.889 Hom.: 136966

Bravo AF: 0.707

TwinsUK AF: 0.927 AC: 3436

ALSPAC AF: 0.919 AC: 3542

ESP6500AA AF: 0.269 AC: 1182

ESP6500EA AF: 0.925 AC: 7948

ExAC AF: 0.864 AC: 104920

Asia WGS AF: 0.854 AC: 2969 AN: 3478

EpiCase AF: 0.924

EpiControl AF: 0.931

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid dyshormonogenesis 6 Benign:4

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	9.6e-7	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.5e-7	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Uncertain	0.30
Sift	Benign	0.043	D;.
Sift4G	Benign	0.075	T;T
Polyphen		0.025	.;B
Vest4		0.23
MPC		0.057
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.31
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs269868; hg19: chr15-45392075; COSMIC: COSV66533432; COSMIC: COSV66533432;