rs199589510

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001363711.2(DUOX2):​c.2653C>T​(p.Arg885*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,974 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

DUOX2
NM_001363711.2 stop_gained, splice_region

Scores

2
3
2
Splicing: ADA: 0.007985
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.987
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 15-45103961-G-A is Pathogenic according to our data. Variant chr15-45103961-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DUOX2NM_001363711.2 linkuse as main transcriptc.2653C>T p.Arg885* stop_gained, splice_region_variant 20/34 ENST00000389039.11 NP_001350640.1
DUOX2NM_014080.5 linkuse as main transcriptc.2653C>T p.Arg885* stop_gained, splice_region_variant 20/34 NP_054799.4 Q9NRD8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DUOX2ENST00000389039.11 linkuse as main transcriptc.2653C>T p.Arg885* stop_gained, splice_region_variant 20/341 NM_001363711.2 ENSP00000373691.7 X6RAN8
DUOX2ENST00000603300.1 linkuse as main transcriptc.2653C>T p.Arg885* stop_gained, splice_region_variant 20/341 ENSP00000475084.1 Q9NRD8
DUOX2ENST00000558383.1 linkuse as main transcriptn.4384C>T splice_region_variant, non_coding_transcript_exon_variant 14/175

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152046
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251460
Hom.:
0
AF XY:
0.0000441
AC XY:
6
AN XY:
135912
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461810
Hom.:
0
Cov.:
32
AF XY:
0.0000358
AC XY:
26
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74382
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000488
Hom.:
0
Bravo
AF:
0.0000793
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Thyroid dyshormonogenesis 6 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaSep 05, 2024- -
Likely pathogenic, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 04, 2024- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 12, 2023This sequence change creates a premature translational stop signal (p.Arg885*) in the DUOX2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DUOX2 are known to be pathogenic (PMID: 12110737, 18765513, 21565790, 24423310, 24735383). This variant is present in population databases (rs199589510, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital hypothyroidism (PMID: 33631011). ClinVar contains an entry for this variant (Variation ID: 225343). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.89
D
Vest4
0.96
GERP RS
0.26

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0080
dbscSNV1_RF
Benign
0.48
SpliceAI score (max)
0.17
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199589510; hg19: chr15-45396159; API