14-80205865-T-C

Position:

• chr14-80205865-T-C

Variant summary

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

The NM_013989.5(DIO2):​c.223-2577A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 453,718 control chromosomes in the GnomAD database, including 52,552 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 (21030 hom., cov: 32)
  • Exomes 𝑓: 0.45 (31522 hom.)
• Consequence: DIO2 NM_013989.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.550

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=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO2	NM_013989.5	c.223-2577A>G		intron_variant		ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257.9	c.223-2577A>G		intron_variant		1	NM_013989.5	ENSP00000405854.5

Frequencies

GnomAD3 genomes AF: 0.513 AC: 78001 AN: 151910 Hom.: 20993 Cov.: 32

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.503

GnomAD4 exome AF: 0.449 AC: 135433 AN: 301690 Hom.: 31522 AF XY: 0.454 AC XY: 71514 AN XY: 157614

Gnomad4 AFR exome AF: 0.652

Gnomad4 AMR exome AF: 0.588

Gnomad4 ASJ exome AF: 0.505

Gnomad4 EAS exome AF: 0.773

Gnomad4 SAS exome AF: 0.533

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.424

Gnomad4 OTH exome AF: 0.466

GnomAD4 genome AF: 0.514 AC: 78093 AN: 152028 Hom.: 21030 Cov.: 32 AF XY: 0.514 AC XY: 38159 AN XY: 74306

Gnomad4 AFR AF: 0.649

Gnomad4 AMR AF: 0.535

Gnomad4 ASJ AF: 0.490

Gnomad4 EAS AF: 0.739

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.383

Gnomad4 NFE AF: 0.430

Gnomad4 OTH AF: 0.505

Alfa AF: 0.451 Hom.: 14293

Bravo AF: 0.533

Asia WGS AF: 0.670 AC: 2328 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.2
DANN	Benign	0.78

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: rs225011; hg19: chr14-80672208; COSMIC: COSV70445225;