rs119472027
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001363711.2(DUOX2):c.2056C>T(p.Gln686Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
DUOX2
NM_001363711.2 stop_gained
NM_001363711.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.17
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-45106217-G-A is Pathogenic according to our data. Variant chr15-45106217-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DUOX2 | NM_001363711.2 | c.2056C>T | p.Gln686Ter | stop_gained | 17/34 | ENST00000389039.11 | |
DUOX2 | NM_014080.5 | c.2056C>T | p.Gln686Ter | stop_gained | 17/34 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DUOX2 | ENST00000389039.11 | c.2056C>T | p.Gln686Ter | stop_gained | 17/34 | 1 | NM_001363711.2 | P4 | |
DUOX2 | ENST00000603300.1 | c.2056C>T | p.Gln686Ter | stop_gained | 17/34 | 1 | A1 | ||
DUOX2 | ENST00000558383.1 | n.3787C>T | non_coding_transcript_exon_variant | 11/17 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251300Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135850
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727232
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Gln686*) 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 (rs119472027, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with iodide organization defect (PMID: 12110737). ClinVar contains an entry for this variant (Variation ID: 4063). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Thyroid dyshormonogenesis 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 11, 2002 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at