Genetic Variant DIO2:c.-143G>A (chr14-80211923-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The ENST00000553968.1(DIO2):c.-143G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 150,126 control chromosomes in the GnomAD database, including 6,993 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6991 hom., cov: 25)

Exomes 𝑓: 0.15 ( 2 hom. )

Consequence

DIO2
ENST00000553968.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.995

Publications

64 publications found

Variant links:

Genes affected

DIO2 (HGNC:2884): (iodothyronine deiodinase 2) The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the conversion of prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4) to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by outer ring 5'-deiodination. This gene is widely expressed, including in thyroid and brain. It is thought to be responsible for the 'local' production of T3, and thus important in influencing thyroid hormone action in these tissues. It has also been reported to be highly expressed in thyroids of patients with Graves disease, and in follicular adenomas. The intrathyroidal T4 to T3 conversion by this enzyme may contribute significantly to the relative increase in thyroidal T3 production in these patients. This protein is a selenoprotein containing the non-standard amino acid, selenocysteine (Sec), which is encoded by the UGA codon that normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. Unlike the other two members (DIO1 and DIO3) of this enzyme family, the mRNA for this gene contains an additional in-frame UGA codon that has been reported (in human) to function either as a Sec or a stop codon, which can result in two isoforms with one or two Sec residues; however, only the upstream Sec (conserved with the single Sec residue found at the active site in DIO1 and DIO3) was shown to be essential for enzyme activity (PMID:10403186). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2018]

DIO2 links:

DIO2-AS1 (HGNC:44153): (DIO2 antisense RNA 1)

DIO2-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein
DIO2	NM_001324462.2 link	c.-143G>A	5_prime_UTR_variant	Exon 1 of 3	NP_001311391.2
DIO2	NM_000793.6 link	c.-53-398G>A	intron_variant	Intron 2 of 3	NP_000784.3
DIO2-AS1	NR_038355.1 link	n.70+435C>T	intron_variant	Intron 1 of 8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein
DIO2	ENST00000553968.1 link	c.-143G>A	5_prime_UTR_variant	Exon 1 of 2	1	ENSP00000451339.1
DIO2-AS1	ENST00000553979.1 link	n.70+435C>T	intron_variant	Intron 1 of 8	1
DIO2	ENST00000557010.5 link	c.-53-398G>A	intron_variant	Intron 2 of 3	2	ENSP00000451419.1

Frequencies

GnomAD3 genomes

AF:

0.273

AC:

40903

AN:

149908

Hom.:

6994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0718

Gnomad AMI

AF:

0.446

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.220

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.373

Gnomad OTH

AF:

0.296

GnomAD4 exome

AF:

0.152

AC:

AN:

112

Hom.:

Cov.:

AF XY:

0.172

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.0833

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.125

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.167

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.189

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.273

AC:

40884

AN:

150014

Hom.:

6991

Cov.:

AF XY:

0.273

AC XY:

19968

AN XY:

73250

show subpopulations

African (AFR)

AF:

0.0715

AC:

2939

AN:

41092

American (AMR)

AF:

0.316

AC:

4764

AN:

15094

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

851

AN:

3450

East Asian (EAS)

AF:

0.153

AC:

777

AN:

5064

South Asian (SAS)

AF:

0.220

AC:

1037

AN:

4722

European-Finnish (FIN)

AF:

0.433

AC:

4261

AN:

9836

Middle Eastern (MID)

AF:

0.329

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.373

AC:

25148

AN:

67482

Other (OTH)

AF:

0.292

AC:

606

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1294

2588

3883

5177

6471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

406

812

1218

1624

2030

<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:

0.333

Hom.:

37691

Bravo

AF:

0.255

Asia WGS

AF:

0.176

AC:

614

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.99

PromoterAI

-0.030

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over