rs225014

Variant names:

• chr14-80203237-T-C
• rs225014
• NM_013989.5:c.274A>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.274A>G​(p.Thr92Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,605,544 control chromosomes in the GnomAD database, including 117,581 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.40 (12048 hom., cov: 27)
  • Exomes 𝑓: 0.38 (105533 hom.)
• Consequence: DIO2 NM_013989.5 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: -0.411
• Publications: 241 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 (MetaRNN=2.324709E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO2	NM_013989.5	c.274A>G	p.Thr92Ala	missense_variant	Exon 2 of 2	ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257.9	c.274A>G	p.Thr92Ala	missense_variant	Exon 2 of 2	1	NM_013989.5	ENSP00000405854.5

Frequencies

GnomAD3 genomes AF: 0.396 AC: 59308 AN: 149900 Hom.: 12021 Cov.: 27

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.410 AC: 97626 AN: 238102 AF XY: 0.407

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.567

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.266

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.392

GnomAD4 exome AF: 0.377 AC: 548354 AN: 1455534 Hom.: 105533 Cov.: 42 AF XY: 0.379 AC XY: 273799 AN XY: 723358

African (AFR) AF: 0.446 AC: 14895 AN: 33414

American (AMR) AF: 0.553 AC: 24246 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 11247 AN: 25960

East Asian (EAS) AF: 0.408 AC: 16119 AN: 39536

South Asian (SAS) AF: 0.480 AC: 40927 AN: 85220

European-Finnish (FIN) AF: 0.271 AC: 14355 AN: 53060

Middle Eastern (MID) AF: 0.353 AC: 2030 AN: 5758

European-Non Finnish (NFE) AF: 0.362 AC: 401293 AN: 1108542

Other (OTH) AF: 0.386 AC: 23242 AN: 60184

GnomAD4 genome AF: 0.396 AC: 59382 AN: 150010 Hom.: 12048 Cov.: 27 AF XY: 0.396 AC XY: 28964 AN XY: 73134

African (AFR) AF: 0.446 AC: 18101 AN: 40542

American (AMR) AF: 0.477 AC: 7217 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1498 AN: 3456

East Asian (EAS) AF: 0.433 AC: 2183 AN: 5040

South Asian (SAS) AF: 0.492 AC: 2330 AN: 4732

European-Finnish (FIN) AF: 0.258 AC: 2610 AN: 10134

Middle Eastern (MID) AF: 0.299 AC: 86 AN: 288

European-Non Finnish (NFE) AF: 0.358 AC: 24234 AN: 67706

Other (OTH) AF: 0.399 AC: 835 AN: 2094

Alfa AF: 0.380 Hom.: 39503

Bravo AF: 0.413

TwinsUK AF: 0.365 AC: 1352

ALSPAC AF: 0.368 AC: 1420

ESP6500AA AF: 0.431 AC: 1725

ESP6500EA AF: 0.367 AC: 3076

ExAC AF: 0.402 AC: 48511

Asia WGS AF: 0.469 AC: 1627 AN: 3478

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Levothyroxine response Other:1

-

Pharmacogenomics/Precision medicine lab, University of Petra

Significance: other

Review Status: no assertion criteria provided

Collection Method: research

- This SNP was not associated with any of thyroid panel hormones in the study

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.088
DANN	Benign	0.57
DEOGEN2	Benign	0.025	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.11	.;T;.
MetaRNN	Benign	0.000023	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.69	N;N;.
PhyloP100		-0.41
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N;N;N
REVEL	Benign	0.0050
Sift	Benign	0.78	T;T;T
Sift4G	Benign	0.77	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.034
MPC		0.24
ClinPred		0.0068	T
GERP RS		-1.4
Varity_R		0.033
Mutation Taster		=99/1	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: rs225014; hg19: chr14-80669580; COSMIC: COSV70445216;