15-45111769-A-G

Variant names:

• chr15-45111769-A-G
• rs199957468
• NM_001363711.2:c.512T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_001363711.2(DUOX2):​c.512T>C​(p.Leu171Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (40 hom., cov: 28)
  • Exomes 𝑓: 0.0027 (63 hom.)
  • Failed GnomAD Quality Control
• Consequence: DUOX2 NM_001363711.2 missense, splice_region
• Scores: Splicing: ADA: 0.00007093
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.59
• Publications: 4 publications found

Genes affected

DUOX2 (HGNC:13273): (dual oxidase 2) The protein encoded by this gene is a glycoprotein and a member of the NADPH oxidase family. The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. This complex contains an iodide transporter, thyroperoxidase, and a peroxide generating system that includes this encoded protein and DUOX1. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. [provided by RefSeq, Jul 2008]

DUOX2 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001363711.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0035519302).
• BP6: Variant 15-45111769-A-G is Benign according to our data. Variant chr15-45111769-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363711.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	NM_001363711.2	MANE Select	c.512T>C	p.Leu171Pro	missense splice_region	Exon 5 of 34	NP_001350640.1
	DUOX2	NM_014080.5		c.512T>C	p.Leu171Pro	missense splice_region	Exon 5 of 34	NP_054799.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.512T>C	p.Leu171Pro	missense splice_region	Exon 5 of 34	ENSP00000373691.7
	DUOX2	ENST00000603300.1	TSL:1	c.512T>C	p.Leu171Pro	missense splice_region	Exon 5 of 34	ENSP00000475084.1
	DUOX2	ENST00000558383.1	TSL:5	n.555T>C		non_coding_transcript_exon	Exon 4 of 17

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1970 AN: 151094 Hom.: 39 Cov.: 28

Gnomad AFR AF: 0.0439

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00505

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000968

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00962

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0121

GnomAD2 exomes AF: 0.00285 AC: 621 AN: 217546 AF XY: 0.00220

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.000325

Gnomad EAS exome AF: 0.000911

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.00223

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00271 AC: 3912 AN: 1443390 Hom.: 63 Cov.: 32 AF XY: 0.00242 AC XY: 1737 AN XY: 716804

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0529 AC: 1726 AN: 32644

American (AMR) AF: 0.00383 AC: 162 AN: 42270

Ashkenazi Jewish (ASJ) AF: 0.00125 AC: 32 AN: 25676

East Asian (EAS) AF: 0.000412 AC: 16 AN: 38798

South Asian (SAS) AF: 0.000711 AC: 60 AN: 84344

European-Finnish (FIN) AF: 0.0000977 AC: 5 AN: 51202

Middle Eastern (MID) AF: 0.00869 AC: 47 AN: 5410

European-Non Finnish (NFE) AF: 0.00143 AC: 1578 AN: 1103550

Other (OTH) AF: 0.00481 AC: 286 AN: 59496

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0131 AC: 1978 AN: 151208 Hom.: 40 Cov.: 28 AF XY: 0.0129 AC XY: 955 AN XY: 73938

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0439 AC: 1785 AN: 40630

American (AMR) AF: 0.00505 AC: 77 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5152

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67960

Other (OTH) AF: 0.0119 AC: 25 AN: 2096

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000864 Hom.: 0

ESP6500AA AF: 0.00985 AC: 42

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.00261 AC: 314

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Thyroid dyshormonogenesis 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.072
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.42
MVP		0.47
MPC		0.65
ClinPred		0.0065	T
GERP RS		1.1
Varity_R		0.15
gMVP		0.84
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000071
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.050		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: rs199957468; hg19: chr15-45403967; COSMIC: COSV106099748; COSMIC: COSV106099748;