NM_001363711.2:c.4239+85T>C

Variant names:

• chr15-45095352-A-G
• rs199138
• NM_001363711.2:c.4239+85T>C

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.4239+85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,582,030 control chromosomes in the GnomAD database, including 645,037 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (47553 hom., cov: 33)
  • Exomes 𝑓: 0.91 (597484 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0160
• Publications: 11 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=-0.88).
• BP6: Variant 15-45095352-A-G is Benign according to our data. Variant chr15-45095352-A-G is described in ClinVar as Benign. ClinVar VariationId is 1283339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.924 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.4239+85T>C		intron	N/A	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.4239+85T>C		intron	N/A	NP_054799.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.4239+85T>C		intron	N/A	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.4239+85T>C		intron	N/A	ENSP00000475084.1	Q9NRD8

Frequencies

GnomAD3 genomes AF: 0.724 AC: 110118 AN: 152122 Hom.: 47565 Cov.: 33

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.856

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.946

Gnomad SAS AF: 0.942

Gnomad FIN AF: 0.921

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.925

Gnomad OTH AF: 0.793

GnomAD4 exome AF: 0.907 AC: 1296932 AN: 1429790 Hom.: 597484 AF XY: 0.911 AC XY: 649469 AN XY: 713290

African (AFR) AF: 0.195 AC: 6381 AN: 32732

American (AMR) AF: 0.865 AC: 38632 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24228 AN: 25946

East Asian (EAS) AF: 0.942 AC: 37265 AN: 39560

South Asian (SAS) AF: 0.938 AC: 80084 AN: 85416

European-Finnish (FIN) AF: 0.931 AC: 48401 AN: 52006

Middle Eastern (MID) AF: 0.931 AC: 5313 AN: 5704

European-Non Finnish (NFE) AF: 0.926 AC: 1004161 AN: 1084394

Other (OTH) AF: 0.884 AC: 52467 AN: 59352

GnomAD4 genome AF: 0.723 AC: 110112 AN: 152240 Hom.: 47553 Cov.: 33 AF XY: 0.733 AC XY: 54539 AN XY: 74446

African (AFR) AF: 0.213 AC: 8861 AN: 41512

American (AMR) AF: 0.856 AC: 13106 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 3230 AN: 3472

East Asian (EAS) AF: 0.946 AC: 4884 AN: 5164

South Asian (SAS) AF: 0.942 AC: 4553 AN: 4834

European-Finnish (FIN) AF: 0.921 AC: 9781 AN: 10616

Middle Eastern (MID) AF: 0.891 AC: 262 AN: 294

European-Non Finnish (NFE) AF: 0.925 AC: 62895 AN: 68016

Other (OTH) AF: 0.790 AC: 1670 AN: 2114

Alfa AF: 0.767 Hom.: 6874

Bravo AF: 0.697

Asia WGS AF: 0.851 AC: 2961 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.58
PhyloP100		0.016
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: rs199138; hg19: chr15-45387550;