14-80211923-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000553968.1(DIO2):c.-143G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 150,126 control chromosomes in the GnomAD database, including 6,993 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 0.27 (6991 hom., cov: 25)
  • Exomes 𝑓: 0.15 (2 hom.)
• Consequence: DIO2 ENST00000553968.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.995

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]

DIO2-AS1 (HGNC:44153): (DIO2 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIO2-AS1	NR_038355.1	n.70+435C>T		intron_variant, non_coding_transcript_variant
DIO2	NM_001324462.2	c.-143G>A		5_prime_UTR_variant	1/3
DIO2	NM_000793.6	c.-53-398G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIO2-AS1	ENST00000553979.1	n.70+435C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 40903 AN: 149908 Hom.: 6994 Cov.: 25

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.296

GnomAD4 exome AF: 0.152 AC: 17 AN: 112 Hom.: 2 Cov.: 0 AF XY: 0.172 AC XY: 10 AN XY: 58

Gnomad4 AFR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.189

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.273 AC: 40884 AN: 150014 Hom.: 6991 Cov.: 25 AF XY: 0.273 AC XY: 19968 AN XY: 73250

Gnomad4 AFR AF: 0.0715

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.292

Alfa AF: 0.343 Hom.: 18831

Bravo AF: 0.255

Asia WGS AF: 0.176 AC: 614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
Cadd	Benign	15
Dann	Benign	0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12885300; hg19: chr14-80678266;