14-80205865-T-C

Variant names:

• chr14-80205865-T-C
• rs225011
• NM_013989.5:c.223-2577A>G

Variant summary

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

The NM_013989.5(DIO2):​c.223-2577A>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
• Publications: 9 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=-0.77).
• 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 rank	MANE	Protein	UniProt
DIO2	NM_013989.5	c.223-2577A>G		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.223-2577A>G		intron_variant	Intron 1 of 1	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

African (AFR) AF: 0.652 AC: 3103 AN: 4762

American (AMR) AF: 0.588 AC: 2156 AN: 3666

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 2436 AN: 4828

East Asian (EAS) AF: 0.773 AC: 3286 AN: 4250

South Asian (SAS) AF: 0.533 AC: 17884 AN: 33566

European-Finnish (FIN) AF: 0.383 AC: 3411 AN: 8914

Middle Eastern (MID) AF: 0.493 AC: 454 AN: 920

European-Non Finnish (NFE) AF: 0.424 AC: 96831 AN: 228190

Other (OTH) AF: 0.466 AC: 5872 AN: 12594

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

African (AFR) AF: 0.649 AC: 26939 AN: 41496

American (AMR) AF: 0.535 AC: 8164 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1697 AN: 3466

East Asian (EAS) AF: 0.739 AC: 3819 AN: 5166

South Asian (SAS) AF: 0.549 AC: 2645 AN: 4816

European-Finnish (FIN) AF: 0.383 AC: 4039 AN: 10554

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29238 AN: 67940

Other (OTH) AF: 0.505 AC: 1067 AN: 2114

Alfa AF: 0.462 Hom.: 19642

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
PhyloP100		-0.55
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: rs225011; hg19: chr14-80672208; COSMIC: COSV70445225;