2-1494031-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.14

Publications

30 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPO links:

ENSG00000231482 (HGNC:):

ENSG00000231482 links:

ENSG00000228613 (HGNC:58132):

ENSG00000228613 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.039).

BP6

Variant 2-1494031-C-T is Benign according to our data. Variant chr2-1494031-C-T is described in ClinVar as Benign. ClinVar VariationId is 256608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.1998C>T	p.Asp666Asp	synonymous_variant	Exon 11 of 17	ENST00000329066.9	NP_001193673.1	P07202-1Q502Y3Q6P534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9 link	c.1998C>T	p.Asp666Asp	synonymous_variant	Exon 11 of 17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.361

AC:

54843

AN:

151852

Hom.:

9964

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.368

AC:

92063

AN:

250454

AF XY:

0.367

show subpopulations

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 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.:

AF XY:

0.367

AC XY:

266775

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.329

AC:

11023

AN:

33472

American (AMR)

AF:

0.385

AC:

17233

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.351

AC:

9171

AN:

26132

East Asian (EAS)

AF:

0.449

AC:

17838

AN:

39696

South Asian (SAS)

AF:

0.376

AC:

32437

AN:

86236

European-Finnish (FIN)

AF:

0.371

AC:

19761

AN:

53326

Middle Eastern (MID)

AF:

0.342

AC:

1973

AN:

5766

European-Non Finnish (NFE)

AF:

0.364

AC:

403999

AN:

1111402

Other (OTH)

AF:

0.371

AC:

22372

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

20195

40390

60586

80781

100976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12872

25744

38616

51488

64360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.361

AC:

54876

AN:

151968

Hom.:

9970

Cov.:

AF XY:

0.362

AC XY:

26900

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.327

AC:

13570

AN:

41468

American (AMR)

AF:

0.404

AC:

6171

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1245

AN:

3472

East Asian (EAS)

AF:

0.415

AC:

2133

AN:

5136

South Asian (SAS)

AF:

0.366

AC:

1760

AN:

4804

European-Finnish (FIN)

AF:

0.373

AC:

3937

AN:

10566

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.365

AC:

24827

AN:

67938

Other (OTH)

AF:

0.368

AC:

778

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1812

3624

5436

7248

9060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

548

1096

1644

2192

2740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.360

Hom.:

21570

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

LINK: link

Submissions by phenotype

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of iodide peroxidase

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.18

(source)

DANN

Benign

0.35

PhyloP100

-5.1

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over