rs2001616

Variant names:

• chr15-45111868-G-A
• rs2001616
• NM_001363711.2:c.413C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-45111868-G-A
• chr15-45111868-G-T

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.413C>T​(p.Pro138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 152,194 control chromosomes in the GnomAD database, including 48,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.77 (48317 hom., cov: 33)
  • Exomes 𝑓: 0.89 (585879 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.47
• Publications: 34 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5484195E-6).
• BP6: Variant 15-45111868-G-A is Benign according to our data. Variant chr15-45111868-G-A is described in ClinVar as Benign. ClinVar VariationId is 260326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.907 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.413C>T	p.Pro138Leu	missense	Exon 5 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.413C>T	p.Pro138Leu	missense	Exon 5 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.413C>T	p.Pro138Leu	missense	Exon 5 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.413C>T	p.Pro138Leu	missense	Exon 5 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.456C>T		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.766 AC: 116562 AN: 152076 Hom.: 48324 Cov.: 33

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.895

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.930

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.863

Gnomad NFE AF: 0.904

Gnomad OTH AF: 0.804

GnomAD2 exomes AF: 0.870 AC: 217090 AN: 249568 AF XY: 0.880

Gnomad AFR exome AF: 0.410

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.901

Gnomad EAS exome AF: 0.910

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.904

Gnomad OTH exome AF: 0.888

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.892 AC: 1303149 AN: 1461378 Hom.: 585879 Cov.: 85 AF XY: 0.894 AC XY: 650240 AN XY: 727006

African (AFR) AF: 0.398 AC: 13321 AN: 33476

American (AMR) AF: 0.856 AC: 38258 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.903 AC: 23582 AN: 26126

East Asian (EAS) AF: 0.894 AC: 35496 AN: 39690

South Asian (SAS) AF: 0.925 AC: 79779 AN: 86252

European-Finnish (FIN) AF: 0.919 AC: 48752 AN: 53052

Middle Eastern (MID) AF: 0.887 AC: 5116 AN: 5766

European-Non Finnish (NFE) AF: 0.905 AC: 1006148 AN: 1111942

Other (OTH) AF: 0.873 AC: 52697 AN: 60384

GnomAD4 genome AF: 0.766 AC: 116575 AN: 152194 Hom.: 48317 Cov.: 33 AF XY: 0.773 AC XY: 57525 AN XY: 74438

African (AFR) AF: 0.416 AC: 17275 AN: 41498

American (AMR) AF: 0.857 AC: 13110 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.895 AC: 3106 AN: 3472

East Asian (EAS) AF: 0.909 AC: 4685 AN: 5154

South Asian (SAS) AF: 0.930 AC: 4490 AN: 4830

European-Finnish (FIN) AF: 0.911 AC: 9677 AN: 10626

Middle Eastern (MID) AF: 0.860 AC: 251 AN: 292

European-Non Finnish (NFE) AF: 0.904 AC: 61470 AN: 67994

Other (OTH) AF: 0.801 AC: 1692 AN: 2112

Alfa AF: 0.863 Hom.: 107138

Bravo AF: 0.747

TwinsUK AF: 0.909 AC: 3372

ALSPAC AF: 0.907 AC: 3495

ESP6500AA AF: 0.430 AC: 1892

ESP6500EA AF: 0.903 AC: 7763

ExAC AF: 0.860 AC: 104343

Asia WGS AF: 0.838 AC: 2915 AN: 3478

EpiCase AF: 0.908

EpiControl AF: 0.910

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.078
Sift	Benign	0.097	T
Sift4G	Benign	0.18	T
Polyphen		0.031	B
Vest4		0.064
MPC		0.40
ClinPred		0.038	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.63
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2001616; hg19: chr15-45404066; COSMIC: COSV59908254; COSMIC: COSV59908254;