NM_207581.4:c.341-15C>T

Variant names:

• chr15-45116501-C-T
• rs2252371
• NM_207581.4:c.341-15C>T

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.341-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,613,064 control chromosomes in the GnomAD database, including 625,633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (45109 hom., cov: 33)
  • Exomes 𝑓: 0.88 (580524 hom.)
• Consequence: DUOXA2 NM_207581.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.550
• Publications: 10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.81).
• BP6: Variant 15-45116501-C-T is Benign according to our data. Variant chr15-45116501-C-T is described in ClinVar as Benign. ClinVar VariationId is 263303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOXA2	NM_207581.4	c.341-15C>T		intron_variant	Intron 3 of 5	ENST00000323030.6	NP_997464.2
DUOXA2	XM_017022180.2	c.377C>T	p.Pro126Leu	missense_variant	Exon 4 of 6		XP_016877669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOXA2	ENST00000323030.6	c.341-15C>T		intron_variant	Intron 3 of 5	1	NM_207581.4	ENSP00000319705.5
DUOXA2	ENST00000491993.2	n.*408-15C>T		intron_variant	Intron 3 of 5	1		ENSP00000454110.1
DUOXA2	ENST00000350243.10	n.621-15C>T		intron_variant	Intron 3 of 4	2

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108005 AN: 151980 Hom.: 45122 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.833

Gnomad ASJ AF: 0.893

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.841

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.760

GnomAD2 exomes AF: 0.853 AC: 211951 AN: 248430 AF XY: 0.865

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.900

Gnomad EAS exome AF: 0.874

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.905

Gnomad OTH exome AF: 0.879

GnomAD4 exome AF: 0.885 AC: 1292681 AN: 1460966 Hom.: 580524 Cov.: 50 AF XY: 0.888 AC XY: 645306 AN XY: 726778

African (AFR) AF: 0.210 AC: 7037 AN: 33460

American (AMR) AF: 0.845 AC: 37787 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23525 AN: 26132

East Asian (EAS) AF: 0.865 AC: 34342 AN: 39690

South Asian (SAS) AF: 0.908 AC: 78308 AN: 86250

European-Finnish (FIN) AF: 0.919 AC: 48488 AN: 52740

Middle Eastern (MID) AF: 0.875 AC: 5048 AN: 5766

European-Non Finnish (NFE) AF: 0.905 AC: 1006341 AN: 1111850

Other (OTH) AF: 0.858 AC: 51805 AN: 60384

GnomAD4 genome AF: 0.710 AC: 107991 AN: 152098 Hom.: 45109 Cov.: 33 AF XY: 0.719 AC XY: 53482 AN XY: 74364

African (AFR) AF: 0.232 AC: 9619 AN: 41474

American (AMR) AF: 0.833 AC: 12744 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 3097 AN: 3470

East Asian (EAS) AF: 0.874 AC: 4506 AN: 5158

South Asian (SAS) AF: 0.908 AC: 4384 AN: 4826

European-Finnish (FIN) AF: 0.911 AC: 9638 AN: 10580

Middle Eastern (MID) AF: 0.836 AC: 244 AN: 292

European-Non Finnish (NFE) AF: 0.902 AC: 61342 AN: 67974

Other (OTH) AF: 0.756 AC: 1600 AN: 2116

Alfa AF: 0.859 Hom.: 61592

Bravo AF: 0.683

Asia WGS AF: 0.804 AC: 2798 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

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:1

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.87
PhyloP100		-0.55
Mutation Taster		=100/0	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: rs2252371; hg19: chr15-45408699;