dbSNP rs143144220: DIO2:p.Val89Val (chr14-80203244-G-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_013989.5(DIO2):c.267C>G(p.Val89Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000845 in 1,604,534 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 6 hom., cov: 29)

Exomes 𝑓: 0.00047 ( 3 hom. )

Consequence

DIO2
NM_013989.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.361

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 14-80203244-G-C is Benign according to our data. Variant chr14-80203244-G-C is described in ClinVar as Benign. ClinVar VariationId is 787950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.361 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013989.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIO2	NM_013989.5	MANE Select	c.267C>G	p.Val89Val	synonymous	Exon 2 of 2	NP_054644.1	Q92813-1
DIO2	NM_000793.6		c.267C>G	p.Val89Val	synonymous	Exon 4 of 4	NP_000784.3
DIO2	NM_001324462.2		c.267C>G	p.Val89Val	synonymous	Exon 3 of 3	NP_001311391.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIO2	ENST00000438257.9	TSL:1 MANE Select	c.267C>G	p.Val89Val	synonymous	Exon 2 of 2	ENSP00000405854.5	Q92813-1
DIO2	ENST00000556811.5	TSL:1	c.*68C>G		3_prime_UTR	Exon 3 of 3	ENSP00000451971.1	H0YJQ8
DIO2	ENST00000555750.2	TSL:1	n.*105C>G		non_coding_transcript_exon	Exon 3 of 3	ENSP00000450980.2	A0A024R6J8

Frequencies

GnomAD3 genomes

AF:

0.00450

AC:

671

AN:

149104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00134

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000633

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00244

GnomAD2 exomes

AF:

0.00109

AC:

259

AN:

237278

AF XY:

0.000871

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.000569

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000849

Gnomad OTH exome

AF:

0.000678

GnomAD4 exome

AF:

0.000468

AC:

681

AN:

1455330

Hom.:

Cov.:

AF XY:

0.000419

AC XY:

303

AN XY:

723226

show subpopulations

African (AFR)

AF:

0.0154

AC:

514

AN:

33396

American (AMR)

AF:

0.000752

AC:

AN:

43872

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25940

East Asian (EAS)

AF:

0.00

AC:

AN:

39504

South Asian (SAS)

AF:

0.0000706

AC:

AN:

85040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53064

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000433

AC:

AN:

1108576

Other (OTH)

AF:

0.00111

AC:

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00452

AC:

675

AN:

149204

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

328

AN XY:

72520

show subpopulations

African (AFR)

AF:

0.0160

AC:

641

AN:

40104

American (AMR)

AF:

0.00134

AC:

AN:

14890

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5046

South Asian (SAS)

AF:

0.000634

AC:

AN:

4732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000885

AC:

AN:

67800

Other (OTH)

AF:

0.00242

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.00529

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.9

(source)

DANN

Benign

0.64

PhyloP100

0.36

Mutation Taster

=98/2

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over