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:6
• 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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

Sel.	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	X6RAN8
	DUOX2	NM_014080.5		c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 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.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.4479C>G	p.Pro1493Pro	synonymous	Exon 33 of 34	ENSP00000475084.1	Q9NRD8

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Thyroid dyshormonogenesis 6 (1)

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;