15-45111769-A-G

Position:

chr15-45111769-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001363711.2(DUOX2):c.512T>C(p.Leu171Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 40 hom., cov: 28)

Exomes 𝑓: 0.0027 ( 63 hom. )

Failed GnomAD Quality Control

Consequence

DUOX2
NM_001363711.2 missense, splice_region

Scores

Splicing: ADA: 0.00007093

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.59

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]

DUOX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035519302).

BP6

Variant 15-45111769-A-G is Benign according to our data. Variant chr15-45111769-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 377229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45111769-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2 link	c.512T>C	p.Leu171Pro	missense_variant, splice_region_variant	5/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5 link	c.512T>C	p.Leu171Pro	missense_variant, splice_region_variant	5/34		NP_054799.4	Q9NRD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOX2	ENST00000389039.11 link	c.512T>C	p.Leu171Pro	missense_variant, splice_region_variant	5/34	1	NM_001363711.2	ENSP00000373691.7	X6RAN8
DUOX2	ENST00000603300.1 link	c.512T>C	p.Leu171Pro	missense_variant, splice_region_variant	5/34	1		ENSP00000475084.1	Q9NRD8
DUOX2	ENST00000558383.1 link	n.555T>C		non_coding_transcript_exon_variant	4/17	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

1970

AN:

151094

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0439

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.000968

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00962

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.0121

GnomAD3 exomes

AF:

0.00285

AC:

621

AN:

217546

Hom.:

AF XY:

0.00220

AC XY:

263

AN XY:

119762

show subpopulations

Gnomad AFR exome

AF:

0.0340

Gnomad AMR exome

AF:

0.00199

Gnomad ASJ exome

AF:

0.000325

Gnomad EAS exome

AF:

0.000911

Gnomad SAS exome

AF:

0.000387

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.00223

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00271

AC:

3912

AN:

1443390

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

1737

AN XY:

716804

show subpopulations

Gnomad4 AFR exome

AF:

0.0529

Gnomad4 AMR exome

AF:

0.00383

Gnomad4 ASJ exome

AF:

0.00125

Gnomad4 EAS exome

AF:

0.000412

Gnomad4 SAS exome

AF:

0.000711

Gnomad4 FIN exome

AF:

0.0000977

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.00481

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0131

AC:

1978

AN:

151208

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

955

AN XY:

73938

show subpopulations

Gnomad4 AFR

AF:

0.0439

Gnomad4 AMR

AF:

0.00505

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00116

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.0119

Alfa

AF:

0.000864

Hom.:

ESP6500AA

AF:

0.00985

AC:

ESP6500EA

AF:

0.000472

AC:

ExAC

AF:

0.00261

AC:

314

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DUOX2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 20, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Thyroid dyshormonogenesis 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.0065

T;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0036

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.29

N;.

REVEL

Benign

0.072

Sift

Benign

0.13

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.0010

.;B

Vest4

0.42

MVP

0.47

MPC

0.65

ClinPred

0.0065

GERP RS

1.1

Varity_R

0.15

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000071

dbscSNV1_RF

Benign

0.030

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over