rs191759494

Variant names:

• chr15-45108159-C-T
• rs191759494
• NM_001363711.2:c.1462G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-45108159-C-T
• chr15-45108159-C-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1 PS3 PP5_Very_Strong

The NM_001363711.2(DUOX2):​c.1462G>A​(p.Gly488Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915683: By assaying hydrogen peroxide production, two independent groups showed the variant protein displays greatly reduced activity compared to the wild type protein in HEK293 and A549 cells (Narumi et al. 2011" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.39
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS1: Transcript NM_001363711.2 (DUOX2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915683: By assaying hydrogen peroxide production, two independent groups showed the variant protein displays greatly reduced activity compared to the wild type protein in HEK293 and A549 cells (Narumi et al. 2011; Jin et al. 2014).; SCV000731474: "In vitro functional studies provide support that the p.Gly488Arg variant impacts protein function (Narumi 2011 and Jin 2015)."; SCV001811087: Published functional studies demonstrate a damaging effect as the generation of H2O2 was significantly reduced in the G488R transfected cells (PMID: 25248169, 21900383); SCV003741498: A hydrogen peroxide production assay showed significantly decreased hydrogen peroxide compared to wild type protein in HEK293 and A549 cells (Narumi, 2011; Jin, 2014).; SCV004114397: This variant was reported in individuals with autosomal recessive congenital hypothyroidism and thyroid dyshormonogenesis, with complete loss of function observed in functional in vitro assays (Narumi et al. 2011. PubMed ID: 21900383; Yoshizawa-Ogasawara et al. 2013. PubMed ID: 23457309; Jin et al. 2014. PubMed ID: 25248169).
• PP5: Variant 15-45108159-C-T is Pathogenic according to our data. Variant chr15-45108159-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 225342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1462G>A	p.Gly488Arg	missense	Exon 13 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.1462G>A	p.Gly488Arg	missense	Exon 13 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.1462G>A	p.Gly488Arg	missense	Exon 13 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.1462G>A	p.Gly488Arg	missense	Exon 13 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.3193G>A		non_coding_transcript_exon	Exon 7 of 17

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152160 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251434 AF XY: 0.000140

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.0000935 AC XY: 68 AN XY: 727234

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00267 AC: 106 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111986

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152278 Hom.: 0 Cov.: 30 AF XY: 0.000228 AC XY: 17 AN XY: 74464

African (AFR) AF: 0.000746 AC: 31 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000152 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Thyroid dyshormonogenesis 6 (4)
1	-	-	DUOX2-related disorder (1)
1	-	-	Familial thyroid dyshormonogenesis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Nongoitrous Euthyroid Hyperthyrotropinemia (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.73		Gain of methylation at G488 (P = 0.0365)
MVP		0.93
MPC		0.40
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.89
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs191759494; hg19: chr15-45400357; COSMIC: COSV66531030;