15-45109895-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001363711.2(DUOX2):c.1126C>G(p.Arg376Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R376W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-45109895-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.1126C>G	p.Arg376Gly	missense_variant	10/34	ENST00000389039.11
DUOX2	NM_014080.5	c.1126C>G	p.Arg376Gly	missense_variant	10/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.1126C>G	p.Arg376Gly	missense_variant	10/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.1126C>G	p.Arg376Gly	missense_variant	10/34	1		A1
DUOX2	ENST00000558383.1	n.1457C>G		non_coding_transcript_exon_variant	7/17	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.059	T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Uncertain	0.39
Sift	Benign	0.042	D;.
Sift4G	Uncertain	0.053	T;T
Polyphen		0.95	.;P
Vest4		0.80
MutPred		0.67		Loss of MoRF binding (P = 0.0414);Loss of MoRF binding (P = 0.0414);
MVP		0.87
MPC		0.42
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs119472029; hg19: chr15-45402093;