rs225010

chr14-80205936-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013989.5(DIO2):c.223-2648G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 151,844 control chromosomes in the GnomAD database, including 20,649 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 0.51 (20649 hom., cov: 31)
• Consequence: DIO2 NM_013989.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIO2	NM_013989.5	c.223-2648G>A		intron_variant		ENST00000438257.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIO2	ENST00000438257.9	c.223-2648G>A		intron_variant		1	NM_013989.5	P1

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77180 AN: 151726 Hom.: 20614 Cov.: 31

Gnomad AFR AF: 0.648

Gnomad AMI AF: 0.403

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.488

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.546

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.494

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

GnomAD4 genome AF: 0.509 AC: 77271 AN: 151844 Hom.: 20649 Cov.: 31 AF XY: 0.509 AC XY: 37768 AN XY: 74190

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.528

Gnomad4 ASJ AF: 0.488

Gnomad4 EAS AF: 0.737

Gnomad4 SAS AF: 0.546

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.423

Gnomad4 OTH AF: 0.495

Alfa AF: 0.464 Hom.: 4518

Bravo AF: 0.528

Asia WGS AF: 0.667 AC: 2318 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.6
Dann	Benign	0.50

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

LitVar

Other links and lift over

dbSNP: rs225010; hg19: chr14-80672279;