15-45106552-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001363711.2(DUOX2):c.1921G>A(p.Glu641Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00513 in 1,614,180 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (21 hom.)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 0.0540

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004345).
• BP6: Variant 15-45106552-C-T is Benign according to our data. Variant chr15-45106552-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418789.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3}.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.1921G>A	p.Glu641Lys	missense_variant	16/34	ENST00000389039.11
DUOX2	NM_014080.5	c.1921G>A	p.Glu641Lys	missense_variant	16/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.1921G>A	p.Glu641Lys	missense_variant	16/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.1921G>A	p.Glu641Lys	missense_variant	16/34	1		A1
DUOX2	ENST00000558383.1	n.3652G>A		non_coding_transcript_exon_variant	10/17	5

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 502 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00559

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00316 AC: 794 AN: 251494 Hom.: 2 AF XY: 0.00297 AC XY: 404 AN XY: 135920

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00532 AC: 7782 AN: 1461878 Hom.: 21 Cov.: 33 AF XY: 0.00520 AC XY: 3780 AN XY: 727236

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00638

Gnomad4 OTH exome AF: 0.00424

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74480

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.00559

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00479 Hom.: 5

Bravo AF: 0.00319

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00570 AC: 49

ExAC AF: 0.00292 AC: 355

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00563

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DUOX2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2022	See Variant Classification Assertion Criteria. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Thyroid dyshormonogenesis 6 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 08, 2017	BS2; BP4; This alteration was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and is predicted to be tolerated by multiple functional prediction tools. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2023	Variant summary: DUOX2 c.1921G>A (p.Glu641Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 251494 control chromosomes in the gnomAD database, including 2 homozygotes suggesting a benign role for this variant. c.1921G>A has been reported in the literature in an individual affected with congenital hypothyroidism with a non-informative genotype and the authors classified the variant as benign (example: de Filippis_2017 and Gentilini_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Thyroid Dyshormonogenesis 6. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

DUOX2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 2022

The DUOX2 c.1921G>A variant is predicted to result in the amino acid substitution p.Glu641Lys. This patient is heterozygous in the DUOX2 gene for a sequence variant designated c.1921G>A, which is predicted to result in the amino acid substitution p.Glu641Lys. This variant has been reported in an individual with a thyroid anomaly who also presented with cleft palate and an atrial septal defect, however an additional variant in a different gene was also reported (CH83, Supplemental Table 3, de Filippis et al. 2017. PubMed ID: 28444304). This variant was identified in multiple individuals participating in a wellness-program and was deemed a variant of unknown physiologic significance (Supplemental table 1, Grasberger et al. 2021. PubMed ID: 33651715). This variant is reported at a subpopulation frequency of ~0.50% (including 2 homozygotes) in a database of individuals of unknown phenotype, which is high for a variant considered to be pathogenic for an autosomal recessive disorder (https://gnomad.broadinstitute.org/variant/15-45398750-C-T). This variant has conflicting interpretations regarding pathogenicity in ClinVar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/418789/). While we suspect that this variant is benign, at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	16
Dann	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.85	N;.
REVEL	Benign	0.038
Sift	Benign	0.40	T;.
Sift4G	Benign	0.44	T;T
Polyphen		0.0020	.;B
Vest4		0.28
MVP		0.84
MPC		0.065
ClinPred		0.0050	T
GERP RS		2.2
Varity_R		0.053
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs139161034; hg19: chr15-45398750; COSMIC: COSV99078249; COSMIC: COSV99078249;