15-45094608-G-C

Variant names:

• chr15-45094608-G-C
• rs56323146
• NM_001363711.2:c.4479C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001363711.2(DUOX2):​c.4479C>G​(p.Pro1493Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0693 in 1,613,836 control chromosomes in the GnomAD database, including 4,205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1493P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.081 (570 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3635 hom.)
• Consequence: DUOX2 NM_001363711.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.751
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 15-45094608-G-C is Benign according to our data. Variant chr15-45094608-G-C is described in ClinVar as Benign. ClinVar VariationId is 260327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.751 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	NP_001350640.1
	DUOX2	NM_014080.5		c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	NP_054799.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	ENSP00000373691.7
	DUOX2	ENST00000603300.1	TSL:1	c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	ENSP00000475084.1

Frequencies

GnomAD3 genomes AF: 0.0808 AC: 12282 AN: 152054 Hom.: 569 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0662

Gnomad ASJ AF: 0.0666

Gnomad EAS AF: 0.0244

Gnomad SAS AF: 0.0501

Gnomad FIN AF: 0.0693

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0687

Gnomad OTH AF: 0.0605

GnomAD2 exomes AF: 0.0653 AC: 16386 AN: 250794 AF XY: 0.0644

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.0726

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.0622

Gnomad NFE exome AF: 0.0660

Gnomad OTH exome AF: 0.0615

GnomAD4 exome AF: 0.0681 AC: 99585 AN: 1461664 Hom.: 3635 Cov.: 32 AF XY: 0.0676 AC XY: 49134 AN XY: 727132

African (AFR) AF: 0.126 AC: 4217 AN: 33478

American (AMR) AF: 0.0748 AC: 3345 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 1696 AN: 26132

East Asian (EAS) AF: 0.0387 AC: 1536 AN: 39696

South Asian (SAS) AF: 0.0527 AC: 4548 AN: 86218

European-Finnish (FIN) AF: 0.0623 AC: 3324 AN: 53386

Middle Eastern (MID) AF: 0.0361 AC: 208 AN: 5766

European-Non Finnish (NFE) AF: 0.0690 AC: 76680 AN: 1111904

Other (OTH) AF: 0.0667 AC: 4031 AN: 60392

GnomAD4 genome AF: 0.0808 AC: 12301 AN: 152172 Hom.: 570 Cov.: 32 AF XY: 0.0796 AC XY: 5922 AN XY: 74394

African (AFR) AF: 0.122 AC: 5082 AN: 41510

American (AMR) AF: 0.0664 AC: 1016 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 231 AN: 3468

East Asian (EAS) AF: 0.0244 AC: 126 AN: 5160

South Asian (SAS) AF: 0.0500 AC: 241 AN: 4822

European-Finnish (FIN) AF: 0.0693 AC: 735 AN: 10606

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4670 AN: 68000

Other (OTH) AF: 0.0632 AC: 133 AN: 2106

Alfa AF: 0.0575 Hom.: 118

Bravo AF: 0.0815

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.0634

EpiControl AF: 0.0573

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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: 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.7
DANN	Benign	0.61
PhyloP100		-0.75
Mutation Taster		=93/7	polymorphism (auto)

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: rs56323146; hg19: chr15-45386806; COSMIC: COSV66534151; COSMIC: COSV66534151;