rs76411432

Variant names:

• chr15-45107335-C-T
• rs76411432
• NM_001363711.2:c.1693+10G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363711.2(DUOX2):​c.1693+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00416 in 1,613,548 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (122 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (90 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.262
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-45107335-C-T is Benign according to our data. Variant chr15-45107335-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0713 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.1693+10G>A		intron	N/A	NP_001350640.1
	DUOX2	NM_014080.5		c.1693+10G>A		intron	N/A	NP_054799.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.1693+10G>A		intron	N/A	ENSP00000373691.7
	DUOX2	ENST00000603300.1	TSL:1	c.1693+10G>A		intron	N/A	ENSP00000475084.1
	DUOX2	ENST00000558383.1	TSL:5	n.3424+10G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3291 AN: 152212 Hom.: 123 Cov.: 31

Gnomad AFR AF: 0.0735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00625 AC: 1573 AN: 251494 AF XY: 0.00470

Gnomad AFR exome AF: 0.0766

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00788

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00234 AC: 3417 AN: 1461218 Hom.: 90 Cov.: 32 AF XY: 0.00207 AC XY: 1506 AN XY: 726996

African (AFR) AF: 0.0736 AC: 2465 AN: 33470

American (AMR) AF: 0.00322 AC: 144 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26128

East Asian (EAS) AF: 0.00388 AC: 154 AN: 39696

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86244

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111402

Other (OTH) AF: 0.00618 AC: 373 AN: 60372

GnomAD4 genome AF: 0.0217 AC: 3298 AN: 152330 Hom.: 122 Cov.: 31 AF XY: 0.0206 AC XY: 1534 AN XY: 74496

African (AFR) AF: 0.0735 AC: 3053 AN: 41562

American (AMR) AF: 0.00902 AC: 138 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00791 AC: 41 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68036

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0156 Hom.: 29

Bravo AF: 0.0245

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	14
DANN	Benign	0.60
PhyloP100		0.26
Mutation Taster		=100/0	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: rs76411432; hg19: chr15-45399533;