NM_001363711.2:c.1461G>C

Variant names:

• chr15-45108160-C-G
• rs269860
• NM_001363711.2:c.1461G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001363711.2(DUOX2):​c.1461G>C​(p.Gly487Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.955 in 1,614,096 control chromosomes in the GnomAD database, including 741,046 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. G487G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.87 (60167 hom., cov: 32)
  • Exomes 𝑓: 0.96 (680879 hom.)
• Consequence: DUOX2 NM_001363711.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.224
• Publications: 13 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 15-45108160-C-G is Benign according to our data. Variant chr15-45108160-C-G is described in ClinVar as Benign. ClinVar VariationId is 260315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.1461G>C	p.Gly487Gly	synonymous_variant	Exon 13 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.1461G>C	p.Gly487Gly	synonymous_variant	Exon 13 of 34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.1461G>C	p.Gly487Gly	synonymous_variant	Exon 13 of 34	1	NM_001363711.2	ENSP00000373691.7
DUOX2	ENST00000603300.1	c.1461G>C	p.Gly487Gly	synonymous_variant	Exon 13 of 34	1		ENSP00000475084.1
DUOX2	ENST00000558383.1	n.3192G>C		non_coding_transcript_exon_variant	Exon 7 of 17	5

Frequencies

GnomAD3 genomes AF: 0.875 AC: 133070 AN: 152104 Hom.: 60155 Cov.: 32

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.992

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 0.977

Gnomad SAS AF: 0.987

Gnomad FIN AF: 0.986

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.972

Gnomad OTH AF: 0.904

GnomAD2 exomes AF: 0.949 AC: 238478 AN: 251416 AF XY: 0.957

Gnomad AFR exome AF: 0.610

Gnomad AMR exome AF: 0.945

Gnomad ASJ exome AF: 0.997

Gnomad EAS exome AF: 0.979

Gnomad FIN exome AF: 0.985

Gnomad NFE exome AF: 0.971

Gnomad OTH exome AF: 0.966

GnomAD4 exome AF: 0.964 AC: 1408581 AN: 1461874 Hom.: 680879 Cov.: 64 AF XY: 0.966 AC XY: 702298 AN XY: 727242

African (AFR) AF: 0.614 AC: 20557 AN: 33480

American (AMR) AF: 0.944 AC: 42231 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26043 AN: 26136

East Asian (EAS) AF: 0.985 AC: 39101 AN: 39700

South Asian (SAS) AF: 0.986 AC: 85035 AN: 86258

European-Finnish (FIN) AF: 0.984 AC: 52572 AN: 53408

Middle Eastern (MID) AF: 0.973 AC: 5615 AN: 5768

European-Non Finnish (NFE) AF: 0.971 AC: 1079753 AN: 1112004

Other (OTH) AF: 0.955 AC: 57674 AN: 60396

GnomAD4 genome AF: 0.875 AC: 133119 AN: 152222 Hom.: 60167 Cov.: 32 AF XY: 0.881 AC XY: 65592 AN XY: 74450

African (AFR) AF: 0.619 AC: 25693 AN: 41488

American (AMR) AF: 0.944 AC: 14443 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3462 AN: 3472

East Asian (EAS) AF: 0.977 AC: 5062 AN: 5180

South Asian (SAS) AF: 0.986 AC: 4764 AN: 4830

European-Finnish (FIN) AF: 0.986 AC: 10473 AN: 10620

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.972 AC: 66126 AN: 68024

Other (OTH) AF: 0.904 AC: 1903 AN: 2106

Alfa AF: 0.942 Hom.: 7566

Bravo AF: 0.859

Asia WGS AF: 0.925 AC: 3216 AN: 3478

EpiCase AF: 0.974

EpiControl AF: 0.973

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

Thyroid dyshormonogenesis 6 Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	4.9
DANN	Benign	0.73
PhyloP100		-0.22
Mutation Taster		=67/33	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: rs269860; hg19: chr15-45400358; COSMIC: COSV66533440;