chr15-45116198-C-T

Variant names:

• chr15-45116198-C-T
• rs1326660372
• NM_207581.4:c.280C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_207581.4(DUOXA2):​c.280C>T​(p.Arg94Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R94H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DUOXA2 NM_207581.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• Publications: 6 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.280C>T	p.Arg94Cys	missense	Exon 3 of 6	NP_997464.2	Q1HG44-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	ENST00000323030.6	TSL:1 MANE Select	c.280C>T	p.Arg94Cys	missense	Exon 3 of 6	ENSP00000319705.5	Q1HG44-1
	DUOXA2	ENST00000491993.2	TSL:1	n.*347C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000454110.1	Q1HG44-2
	DUOXA2	ENST00000491993.2	TSL:1	n.*347C>T		3_prime_UTR	Exon 3 of 6	ENSP00000454110.1	Q1HG44-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 53 AF XY: 0.00 AC XY: 0 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.22
Sift	Benign	0.055	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.45
MutPred		0.44		Loss of MoRF binding (P = 0.0031)
MVP		0.50
MPC		0.26
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.16
gMVP		0.77
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1326660372; hg19: chr15-45408396;