15-45106171-C-T

Variant names:

• chr15-45106171-C-T
• rs113400262
• NM_001363711.2:c.2102G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363711.2(DUOX2):​c.2102G>A​(p.Arg701Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0548 in 1,614,058 control chromosomes in the GnomAD database, including 2,712 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R701L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.049 (237 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2475 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.38
• Publications: 14 publications found

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]

DUOX2 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001822114).
• BP6: Variant 15-45106171-C-T is Benign according to our data. Variant chr15-45106171-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.2102G>A	p.Arg701Gln	missense_variant	Exon 17 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.2102G>A	p.Arg701Gln	missense_variant	Exon 17 of 34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.2102G>A	p.Arg701Gln	missense_variant	Exon 17 of 34	1	NM_001363711.2	ENSP00000373691.7
DUOX2	ENST00000603300.1	c.2102G>A	p.Arg701Gln	missense_variant	Exon 17 of 34	1		ENSP00000475084.1
DUOX2	ENST00000558383.1	n.3833G>A		non_coding_transcript_exon_variant	Exon 11 of 17	5

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 7483 AN: 152100 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0740

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0647

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0582

Gnomad OTH AF: 0.0508

GnomAD2 exomes AF: 0.0525 AC: 13188 AN: 251334 AF XY: 0.0532

Gnomad AFR exome AF: 0.0295

Gnomad AMR exome AF: 0.0720

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0588

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0574

GnomAD4 exome AF: 0.0554 AC: 80962 AN: 1461840 Hom.: 2475 Cov.: 33 AF XY: 0.0554 AC XY: 40255 AN XY: 727220

African (AFR) AF: 0.0313 AC: 1047 AN: 33480

American (AMR) AF: 0.0733 AC: 3279 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 1899 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.0431 AC: 3719 AN: 86254

European-Finnish (FIN) AF: 0.0573 AC: 3058 AN: 53412

Middle Eastern (MID) AF: 0.0671 AC: 387 AN: 5768

European-Non Finnish (NFE) AF: 0.0579 AC: 64365 AN: 1111974

Other (OTH) AF: 0.0529 AC: 3197 AN: 60396

GnomAD4 genome AF: 0.0492 AC: 7490 AN: 152218 Hom.: 237 Cov.: 32 AF XY: 0.0491 AC XY: 3655 AN XY: 74424

African (AFR) AF: 0.0309 AC: 1282 AN: 41544

American (AMR) AF: 0.0604 AC: 923 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0740 AC: 257 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0401 AC: 193 AN: 4812

European-Finnish (FIN) AF: 0.0647 AC: 686 AN: 10600

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0583 AC: 3962 AN: 68004

Other (OTH) AF: 0.0502 AC: 106 AN: 2110

Alfa AF: 0.0537 Hom.: 481

Bravo AF: 0.0484

TwinsUK AF: 0.0534 AC: 198

ALSPAC AF: 0.0566 AC: 218

ESP6500AA AF: 0.0318 AC: 140

ESP6500EA AF: 0.0587 AC: 505

ExAC AF: 0.0504 AC: 6120

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0570

EpiControl AF: 0.0550

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28666341) -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thyroid dyshormonogenesis 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		-1.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.96	N;.
REVEL	Benign	0.058
Sift	Benign	0.21	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.17	.;B
Vest4		0.042
MPC		0.095
ClinPred		0.0050	T
GERP RS		-2.0
Varity_R		0.043
gMVP		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113400262; hg19: chr15-45398369; COSMIC: COSV107487916; COSMIC: COSV107487916;