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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363711.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.2033A>G	p.His678Arg	missense	Exon 17 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.2033A>G	p.His678Arg	missense	Exon 17 of 34	NP_054799.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.2033A>G	p.His678Arg	missense	Exon 17 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.2033A>G	p.His678Arg	missense	Exon 17 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.3764A>G		non_coding_transcript_exon	Exon 11 of 17

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Thyroid dyshormonogenesis 6 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.022	T
MetaRNN	Benign	0.0028	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
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;