15-45111501-C-T

Variant names:

• chr15-45111501-C-T
• rs2467827
• NM_001363711.2:c.598G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001363711.2(DUOX2):​c.598G>A​(p.Gly200Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,551,330 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (5 hom., cov: 28)
  • Exomes 𝑓: 0.0013 (12 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 1.13
• Publications: 4 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014877588).
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.598G>A	p.Gly200Arg	missense	Exon 6 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.598G>A	p.Gly200Arg	missense	Exon 6 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.598G>A	p.Gly200Arg	missense	Exon 6 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.598G>A	p.Gly200Arg	missense	Exon 6 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.823G>A		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 151790 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.000906 AC: 135 AN: 149026 AF XY: 0.000971

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.000599

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000708

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000941

GnomAD4 exome AF: 0.00131 AC: 1839 AN: 1399434 Hom.: 12 Cov.: 32 AF XY: 0.00133 AC XY: 918 AN XY: 691094

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00172 AC: 54 AN: 31316

American (AMR) AF: 0.000800 AC: 29 AN: 36272

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 25074

East Asian (EAS) AF: 0.00 AC: 0 AN: 36126

South Asian (SAS) AF: 0.00191 AC: 152 AN: 79586

European-Finnish (FIN) AF: 0.000108 AC: 5 AN: 46096

Middle Eastern (MID) AF: 0.00590 AC: 24 AN: 4070

European-Non Finnish (NFE) AF: 0.00137 AC: 1485 AN: 1083022

Other (OTH) AF: 0.00150 AC: 87 AN: 57872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00144 AC: 219 AN: 151896 Hom.: 5 Cov.: 28 AF XY: 0.00132 AC XY: 98 AN XY: 74262

African (AFR) AF: 0.00177 AC: 73 AN: 41170

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00162 AC: 110 AN: 68018

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00138 Hom.: 1

Bravo AF: 0.00169

ExAC AF: 0.000287 AC: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
1	-	-	Congenital hypothyroidism (1)
-	1	-	Familial thyroid dyshormonogenesis;C4749351:Genetic transient congenital hypothyroidism (1)
-	1	-	not specified (1)
-	1	-	Thyroid dyshormonogenesis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.16	T
Sift4G	Benign	0.24	T
Polyphen		0.049	B
Vest4		0.33
MutPred		0.65		Gain of solvent accessibility (P = 0.0097)
MVP		0.61
MPC		0.59
ClinPred		0.020	T
GERP RS		3.2
Varity_R		0.18
gMVP		0.46
Mutation Taster		=92/8	polymorphism

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: rs2467827; hg19: chr15-45403699;