2-1494031-C-T

Position:

• chr2-1494031-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001206744.2(TPO):​c.1998C>T​(p.Asp666Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,613,066 control chromosomes in the GnomAD database, including 108,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9970 hom., cov: 32)
  • Exomes 𝑓: 0.37 (98914 hom.)
• Consequence: TPO NM_001206744.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -5.14

Genes affected

TPO (HGNC:12015): (thyroid peroxidase) This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]

TPO (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-1494031-C-T is Benign according to our data. Variant chr2-1494031-C-T is described in ClinVar as [Benign]. Clinvar id is 256608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1494031-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2	c.1998C>T	p.Asp666Asp	synonymous_variant	11/17	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.1998C>T	p.Asp666Asp	synonymous_variant	11/17	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54843 AN: 151852 Hom.: 9964 Cov.: 32

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.368 AC: 92063 AN: 250454 Hom.: 17001 AF XY: 0.367 AC XY: 49776 AN XY: 135510

Gnomad AFR exome AF: 0.321

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.350

Gnomad EAS exome AF: 0.411

Gnomad SAS exome AF: 0.378

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.365

GnomAD4 exome AF: 0.367 AC: 535807 AN: 1461098 Hom.: 98914 Cov.: 42 AF XY: 0.367 AC XY: 266775 AN XY: 726928

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.385

Gnomad4 ASJ exome AF: 0.351

Gnomad4 EAS exome AF: 0.449

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.371

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.361 AC: 54876 AN: 151968 Hom.: 9970 Cov.: 32 AF XY: 0.362 AC XY: 26900 AN XY: 74280

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.365

Gnomad4 OTH AF: 0.368

Alfa AF: 0.361 Hom.: 15458

Bravo AF: 0.360

Asia WGS AF: 0.382 AC: 1327 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.360

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Deficiency of iodide peroxidase Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.18
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1126797; hg19: chr2-1497803; COSMIC: COSV61102057;