15-45116216-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207581.4(DUOXA2):c.298C>G(p.Arg100Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.977 in 1,613,990 control chromosomes in the GnomAD database, including 777,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (61048 hom., cov: 32)
  • Exomes 𝑓: 0.99 (716472 hom.)
• Consequence: DUOXA2 NM_207581.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.48

Genes affected

DUOXA2 (HGNC:32698): (dual oxidase maturation factor 2) This gene encodes an endoplasmic reticulum protein that is necessary for proper cellular localization and maturation of functional dual oxidase 2. Mutations in this gene have been associated with thyroid dyshormonogenesis 5.[provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2533039E-6).
• BP6: Variant 15-45116216-C-G is Benign according to our data. Variant chr15-45116216-C-G is described in ClinVar as [Benign]. Clinvar id is 263302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45116216-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOXA2	NM_207581.4	c.298C>G	p.Arg100Gly	missense_variant	3/6	ENST00000323030.6
DUOXA2	XM_017022180.2	c.298C>G	p.Arg100Gly	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOXA2	ENST00000323030.6	c.298C>G	p.Arg100Gly	missense_variant	3/6	1	NM_207581.4	P1
DUOXA2	ENST00000491993.2	c.*365C>G		3_prime_UTR_variant, NMD_transcript_variant	3/6	1
DUOXA2	ENST00000350243.10	n.578C>G		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132879 AN: 152034 Hom.: 61037 Cov.: 32

Gnomad AFR AF: 0.557

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.911

GnomAD3 exomes AF: 0.969 AC: 241874 AN: 249510 Hom.: 118692 AF XY: 0.977 AC XY: 132260 AN XY: 135382

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.985

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.990

GnomAD4 exome AF: 0.988 AC: 1443770 AN: 1461838 Hom.: 716472 Cov.: 73 AF XY: 0.989 AC XY: 719544 AN XY: 727210

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.982

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.974

GnomAD4 genome AF: 0.874 AC: 132937 AN: 152152 Hom.: 61048 Cov.: 32 AF XY: 0.880 AC XY: 65467 AN XY: 74390

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.961

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.912

Alfa AF: 0.924 Hom.: 17856

Bravo AF: 0.857

TwinsUK AF: 0.999 AC: 3706

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.584 AC: 2331

ESP6500EA AF: 0.999 AC: 8287

ExAC AF: 0.962 AC: 116215

Asia WGS AF: 0.977 AC: 3396 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Thyroglobulin synthesis defect Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.034
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	16
Dann	Benign	0.56
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.4	N
MutationTaster	Benign	0.99	P
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	7.0	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.22
ClinPred		0.0073	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2576090; hg19: chr15-45408414;