chr15-45116216-C-G

Variant names:

• chr15-45116216-C-G
• rs2576090
• NM_207581.4:c.298C>G

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.48
• Publications: 25 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	NM_207581.4	MANE Select	c.298C>G	p.Arg100Gly	missense	Exon 3 of 6	NP_997464.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	ENST00000323030.6	TSL:1 MANE Select	c.298C>G	p.Arg100Gly	missense	Exon 3 of 6	ENSP00000319705.5
	DUOXA2	ENST00000491993.2	TSL:1	n.*365C>G		non_coding_transcript_exon	Exon 3 of 6	ENSP00000454110.1
	DUOXA2	ENST00000491993.2	TSL:1	n.*365C>G		3_prime_UTR	Exon 3 of 6	ENSP00000454110.1

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

GnomAD2 exomes AF: 0.969 AC: 241874 AN: 249510 AF XY: 0.977

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

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

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

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

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Thyroglobulin synthesis defect (2)

Computational scores

Source: dbNSFP v4.9

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

Other links and lift over

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