14-80205865-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_013989.5(DIO2):​c.223-2577A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013989.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO2	NM_013989.5	MANE Select	c.223-2577A>T		intron	N/A	NP_054644.1
	DIO2	NM_000793.6		c.223-2577A>T		intron	N/A	NP_000784.3
	DIO2	NM_001324462.2		c.223-2577A>T		intron	N/A	NP_001311391.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO2	ENST00000438257.9	TSL:1 MANE Select	c.223-2577A>T		intron	N/A	ENSP00000405854.5
	DIO2	ENST00000556811.5	TSL:1	c.64-130A>T		intron	N/A	ENSP00000451971.1
	DIO2	ENST00000555750.2	TSL:1	n.*60+366A>T		intron	N/A	ENSP00000450980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 302596 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 158082

African (AFR) AF: 0.00 AC: 0 AN: 4770

American (AMR) AF: 0.00 AC: 0 AN: 3674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4842

East Asian (EAS) AF: 0.00 AC: 0 AN: 4256

South Asian (SAS) AF: 0.00 AC: 0 AN: 33626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 922

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228978

Other (OTH) AF: 0.00 AC: 0 AN: 12610

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 19642

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.9
DANN	Benign	0.83
PhyloP100		-0.55

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;