14-80203586-T-G

Variant names:

• chr14-80203586-T-G
• rs225013
• NM_013989.5:c.223-298A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013989.5(DIO2):​c.223-298A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 152,104 control chromosomes in the GnomAD database, including 26,893 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 0.57 (26893 hom., cov: 33)
• Consequence: DIO2 NM_013989.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.620
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO2	NM_013989.5	c.223-298A>C		intron_variant	Intron 1 of 1	ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257.9	c.223-298A>C		intron_variant	Intron 1 of 1	1	NM_013989.5	ENSP00000405854.5

Frequencies

GnomAD3 genomes AF: 0.574 AC: 87310 AN: 151986 Hom.: 26835 Cov.: 33

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.743

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.393

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.552

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.575 AC: 87427 AN: 152104 Hom.: 26893 Cov.: 33 AF XY: 0.573 AC XY: 42608 AN XY: 74358

African (AFR) AF: 0.789 AC: 32727 AN: 41490

American (AMR) AF: 0.566 AC: 8645 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1848 AN: 3470

East Asian (EAS) AF: 0.742 AC: 3844 AN: 5178

South Asian (SAS) AF: 0.595 AC: 2862 AN: 4814

European-Finnish (FIN) AF: 0.393 AC: 4159 AN: 10576

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31682 AN: 67980

Other (OTH) AF: 0.553 AC: 1167 AN: 2110

Alfa AF: 0.501 Hom.: 32204

Bravo AF: 0.599

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.44
DANN	Benign	0.75
PhyloP100		-0.62
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: rs225013; hg19: chr14-80669929;