15-45111852-G-T

Variant names:

• chr15-45111852-G-T
• rs7166994
• NM_001363711.2:c.429C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001363711.2(DUOX2):​c.429C>A​(p.Asp143Glu) 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 benign outcome for this variant. 17/22 in silico tools predict a benign 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. D143Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 28)
• Consequence: DUOX2 NM_001363711.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044376075).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.429C>A	p.Asp143Glu	missense_variant	Exon 5 of 34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.429C>A	p.Asp143Glu	missense_variant	Exon 5 of 34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.429C>A	p.Asp143Glu	missense_variant	Exon 5 of 34	1	NM_001363711.2	ENSP00000373691.7
DUOX2	ENST00000603300.1	c.429C>A	p.Asp143Glu	missense_variant	Exon 5 of 34	1		ENSP00000475084.1
DUOX2	ENST00000558383.1	n.472C>A		non_coding_transcript_exon_variant	Exon 4 of 17	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	.;L
PhyloP100		-0.069
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.52	N;.
REVEL	Benign	0.11
Sift	Benign	0.51	T;.
Sift4G	Benign	0.63	T;T
Polyphen		0.014	.;B
Vest4		0.055
MutPred		0.33		Gain of catalytic residue at D143 (P = 0.0906);Gain of catalytic residue at D143 (P = 0.0906);
MVP		0.54
MPC		0.36
ClinPred		0.15	T
GERP RS		4.3
Varity_R		0.051
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs7166994; hg19: chr15-45404050;