rs225014

Positions:

• chr14-80203237-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.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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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 (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/exons	MANE	Protein	UniProt
DIO2	NM_013989.5	c.274A>G	p.Thr92Ala	missense_variant	2/2	ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257.9	c.274A>G	p.Thr92Ala	missense_variant	2/2	1	NM_013989.5	ENSP00000405854	P1

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

GnomAD3 exomes AF: 0.410 AC: 97626 AN: 238102 Hom.: 21011 AF XY: 0.407 AC XY: 52426 AN XY: 128910

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 SAS exome AF: 0.486

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

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.480

Gnomad4 FIN exome AF: 0.271

Gnomad4 NFE exome AF: 0.362

Gnomad4 OTH exome AF: 0.386

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

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.399

Alfa AF: 0.373 Hom.: 26326

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

other, no assertion criteria provided

research

Pharmacogenomics/Precision medicine lab, University of Petra

-

- 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;.
MutationTaster	Benign	1.0	P;P;P;P;P
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

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: rs225014; hg19: chr14-80669580; COSMIC: COSV70445216;