15-45111769-A-T

Position:

• chr15-45111769-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001363711.2(DUOX2):​c.512T>A​(p.Leu171Gln) variant causes a missense, splice region 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. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. L171P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: DUOX2 NM_001363711.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004543
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046661317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.512T>A	p.Leu171Gln	missense_variant, splice_region_variant	5/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.512T>A	p.Leu171Gln	missense_variant, splice_region_variant	5/34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.512T>A	p.Leu171Gln	missense_variant, splice_region_variant	5/34	1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1	c.512T>A	p.Leu171Gln	missense_variant, splice_region_variant	5/34	1		ENSP00000475084	A1
DUOX2	ENST00000558383.1	n.555T>A		non_coding_transcript_exon_variant	4/17	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.0072	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.047	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.6	.;N
MutationTaster	Benign	0.61	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	3.8	N;.
REVEL	Benign	0.069
Sift	Benign	0.71	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	.;B
Vest4		0.28
MutPred		0.55		Gain of disorder (P = 0.0211);Gain of disorder (P = 0.0211);
MVP		0.25
MPC		0.45
ClinPred		0.058	T
GERP RS		1.1
Varity_R		0.10
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.088
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: rs199957468; hg19: chr15-45403967; COSMIC: COSV105237650; COSMIC: COSV105237650;