NM_207581.4:c.298C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 13/21 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

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.48

Publications

25 publications found
Variant links:
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]
DUOXA2 Gene-Disease associations (from GenCC):
  • thyroid dyshormonogenesis 5
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • familial thyroid dyshormonogenesis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 CliVar 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 CliVar 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 CliVar as Benign. Clinvar id is 263302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
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 rank MANE Protein UniProt
DUOXA2NM_207581.4 linkc.298C>G p.Arg100Gly missense_variant Exon 3 of 6 ENST00000323030.6 NP_997464.2 Q1HG44-1
DUOXA2XM_017022180.2 linkc.298C>G p.Arg100Gly missense_variant Exon 3 of 6 XP_016877669.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DUOXA2ENST00000323030.6 linkc.298C>G p.Arg100Gly missense_variant Exon 3 of 6 1 NM_207581.4 ENSP00000319705.5 Q1HG44-1
DUOXA2ENST00000491993.2 linkn.*365C>G non_coding_transcript_exon_variant Exon 3 of 6 1 ENSP00000454110.1 Q1HG44-2
DUOXA2ENST00000491993.2 linkn.*365C>G 3_prime_UTR_variant Exon 3 of 6 1 ENSP00000454110.1 Q1HG44-2
DUOXA2ENST00000350243.10 linkn.578C>G non_coding_transcript_exon_variant Exon 3 of 5 2

Frequencies

GnomAD3 genomes
AF:
0.874
AC:
132879
AN:
152034
Hom.:
61037
Cov.:
32
show subpopulations
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
GnomAD2 exomes
AF:
0.969
AC:
241874
AN:
249510
AF XY:
0.977
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.549
AC:
18397
AN:
33480
American (AMR)
AF:
0.982
AC:
43903
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
1.00
AC:
26135
AN:
26136
East Asian (EAS)
AF:
1.00
AC:
39700
AN:
39700
South Asian (SAS)
AF:
0.999
AC:
86202
AN:
86258
European-Finnish (FIN)
AF:
1.00
AC:
53367
AN:
53368
Middle Eastern (MID)
AF:
0.990
AC:
5710
AN:
5768
European-Non Finnish (NFE)
AF:
1.00
AC:
1111530
AN:
1112010
Other (OTH)
AF:
0.974
AC:
58826
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.468
Heterozygous variant carriers
0
696
1393
2089
2786
3482
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
21614
43228
64842
86456
108070
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.874
AC:
132937
AN:
152152
Hom.:
61048
Cov.:
32
AF XY:
0.880
AC XY:
65467
AN XY:
74390
show subpopulations
African (AFR)
AF:
0.557
AC:
23073
AN:
41428
American (AMR)
AF:
0.961
AC:
14708
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
1.00
AC:
3472
AN:
3472
East Asian (EAS)
AF:
1.00
AC:
5162
AN:
5162
South Asian (SAS)
AF:
0.999
AC:
4816
AN:
4820
European-Finnish (FIN)
AF:
1.00
AC:
10618
AN:
10618
Middle Eastern (MID)
AF:
0.986
AC:
290
AN:
294
European-Non Finnish (NFE)
AF:
0.999
AC:
67959
AN:
68030
Other (OTH)
AF:
0.912
AC:
1927
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
564
1129
1693
2258
2822
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
868
1736
2604
3472
4340
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Thyroglobulin synthesis defect Benign:2
May 28, 2019
Mendelics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jul 05, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
PhyloP100
7.5
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
Mutation Taster
=98/2
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2576090; hg19: chr15-45408414; COSMIC: COSV107261575; COSMIC: COSV107261575; API