rs57659670

Variant names:

• chr15-45106240-T-C
• rs57659670
• NM_001363711.2:c.2033A>G

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.2033A>G​(p.His678Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0909 in 1,613,922 control chromosomes in the GnomAD database, including 10,798 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (3586 hom., cov: 32)
  • Exomes 𝑓: 0.083 (7212 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0520
• Publications: 48 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=0.0027880967).
• BP6: Variant 15-45106240-T-C is Benign according to our data. Variant chr15-45106240-T-C is described in ClinVar as Benign. ClinVar VariationId is 260317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.2033A>G	p.His678Arg	missense_variant	Exon 17 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.2033A>G	p.His678Arg	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.2033A>G	p.His678Arg	missense_variant	Exon 17 of 34	1	NM_001363711.2	ENSP00000373691.7
DUOX2	ENST00000603300.1	c.2033A>G	p.His678Arg	missense_variant	Exon 17 of 34	1		ENSP00000475084.1
DUOX2	ENST00000558383.1	n.3764A>G		non_coding_transcript_exon_variant	Exon 11 of 17	5

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24856 AN: 151996 Hom.: 3571 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.0513

Gnomad SAS AF: 0.0560

Gnomad FIN AF: 0.0762

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0751

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.0977 AC: 24527 AN: 251162 AF XY: 0.0907

Gnomad AFR exome AF: 0.390

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0813

Gnomad EAS exome AF: 0.0502

Gnomad FIN exome AF: 0.0686

Gnomad NFE exome AF: 0.0738

Gnomad OTH exome AF: 0.0880

GnomAD4 exome AF: 0.0833 AC: 121760 AN: 1461810 Hom.: 7212 Cov.: 33 AF XY: 0.0816 AC XY: 59325 AN XY: 727210

African (AFR) AF: 0.401 AC: 13423 AN: 33478

American (AMR) AF: 0.122 AC: 5472 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0791 AC: 2068 AN: 26136

East Asian (EAS) AF: 0.0554 AC: 2200 AN: 39700

South Asian (SAS) AF: 0.0600 AC: 5177 AN: 86258

European-Finnish (FIN) AF: 0.0682 AC: 3644 AN: 53392

Middle Eastern (MID) AF: 0.0940 AC: 542 AN: 5766

European-Non Finnish (NFE) AF: 0.0750 AC: 83403 AN: 1111970

Other (OTH) AF: 0.0966 AC: 5831 AN: 60392

GnomAD4 genome AF: 0.164 AC: 24920 AN: 152112 Hom.: 3586 Cov.: 32 AF XY: 0.160 AC XY: 11894 AN XY: 74370

African (AFR) AF: 0.386 AC: 16009 AN: 41440

American (AMR) AF: 0.117 AC: 1783 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0853 AC: 296 AN: 3470

East Asian (EAS) AF: 0.0512 AC: 265 AN: 5176

South Asian (SAS) AF: 0.0564 AC: 272 AN: 4820

European-Finnish (FIN) AF: 0.0762 AC: 807 AN: 10596

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0751 AC: 5110 AN: 68000

Other (OTH) AF: 0.141 AC: 299 AN: 2114

Alfa AF: 0.100 Hom.: 4261

Bravo AF: 0.176

TwinsUK AF: 0.0701 AC: 260

ALSPAC AF: 0.0763 AC: 294

ESP6500AA AF: 0.388 AC: 1705

ESP6500EA AF: 0.0753 AC: 647

ExAC AF: 0.102 AC: 12389

Asia WGS AF: 0.115 AC: 399 AN: 3478

EpiCase AF: 0.0736

EpiControl AF: 0.0684

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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: 25248169, 24423310, 21900383, 20981092, 25616291, 18765513, 27884173, 23239635, 25263060, 26565538, 21565790, 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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.12
DANN	Benign	0.24
DEOGEN2	Benign	0.0050	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.022	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.3	.;N
PhyloP100		-0.052
PrimateAI	Benign	0.21	T
PROVEAN	Benign	2.1	N;.
REVEL	Benign	0.096
Sift	Benign	1.0	T;.
Sift4G	Benign	0.91	T;T
Polyphen		0.0	.;B
Vest4		0.050
MPC		0.069
ClinPred		0.0029	T
GERP RS		-0.37
Varity_R		0.023
gMVP		0.10
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: rs57659670; hg19: chr15-45398438; COSMIC: COSV66534179; COSMIC: COSV66534179;