rs2001616

chr15-45111868-G-Achr15-45111868-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.413C>T(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,194 control chromosomes in the GnomAD database, including 48,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.77 (48317 hom., cov: 33)
  • Exomes 𝑓: 0.89 (585879 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.47

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=1.5484195E-6).
• BP6: Variant 15-45111868-G-A is Benign according to our data. Variant chr15-45111868-G-A is described in ClinVar as [Benign]. Clinvar id is 260326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45111868-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.413C>T	p.Pro138Leu	missense_variant	5/34	ENST00000389039.11
DUOX2	NM_014080.5	c.413C>T	p.Pro138Leu	missense_variant	5/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.413C>T	p.Pro138Leu	missense_variant	5/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.413C>T	p.Pro138Leu	missense_variant	5/34	1		A1
DUOX2	ENST00000558383.1	n.456C>T		non_coding_transcript_exon_variant	4/17	5

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116562 AN: 152076 Hom.: 48324 Cov.: 33

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.930

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.863

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.804

GnomAD3 exomes AF: 0.870 AC: 217090 AN: 249568 Hom.: 96466 AF XY: 0.880 AC XY: 119118 AN XY: 135384

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.910

Gnomad SAS exome AF: 0.924

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.904

Gnomad OTH exome AF: 0.888

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.892 AC: 1303149 AN: 1461378 Hom.: 585879 Cov.: 85 AF XY: 0.894 AC XY: 650240 AN XY: 727006

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.856

Gnomad4 ASJ exome AF: 0.903

Gnomad4 EAS exome AF: 0.894

Gnomad4 SAS exome AF: 0.925

Gnomad4 FIN exome AF: 0.919

Gnomad4 NFE exome AF: 0.905

Gnomad4 OTH exome AF: 0.873

GnomAD4 genome AF: 0.766 AC: 116575 AN: 152194 Hom.: 48317 Cov.: 33 AF XY: 0.773 AC XY: 57525 AN XY: 74438

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.895

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.930

Gnomad4 FIN AF: 0.911

Gnomad4 NFE AF: 0.904

Gnomad4 OTH AF: 0.801

Alfa AF: 0.843 Hom.: 34763

Bravo AF: 0.747

TwinsUK AF: 0.909 AC: 3372

ALSPAC AF: 0.907 AC: 3495

ESP6500AA AF: 0.430 AC: 1892

ESP6500EA AF: 0.903 AC: 7763

ExAC AF: 0.860 AC: 104343

Asia WGS AF: 0.838 AC: 2915 AN: 3478

EpiCase AF: 0.908

EpiControl AF: 0.910

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid dyshormonogenesis 6 Benign:3

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

not specified Benign:2

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

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	0.086
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.0000071	P
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D;.
REVEL	Benign	0.078
Sift	Benign	0.097	T;.
Sift4G	Benign	0.18	T;T
Polyphen		0.031	.;B
Vest4		0.064
MPC		0.40
ClinPred		0.038	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs2001616; hg19: chr15-45404066; COSMIC: COSV59908254; COSMIC: COSV59908254;