rs1126797

Variant names:

• chr2-1494031-C-T
• rs1126797
• NM_001206744.2:c.1998C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-1494031-C-T
• chr2-1494031-C-A
• chr2-1494031-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate 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
• Publications: 30 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

LALTOP (HGNC:58132):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206744.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	NM_001206744.2	MANE Select	c.1998C>T	p.Asp666Asp	synonymous	Exon 11 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.1998C>T	p.Asp666Asp	synonymous	Exon 11 of 17	NP_000538.3
	TPO	NM_175721.3		c.1998C>T	p.Asp666Asp	synonymous	Exon 10 of 15	NP_783652.1	P07202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.1998C>T	p.Asp666Asp	synonymous	Exon 11 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.1998C>T	p.Asp666Asp	synonymous	Exon 11 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.1827C>T	p.Asp609Asp	synonymous	Exon 10 of 16	ENSP00000371636.3	P07202-2

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

GnomAD2 exomes AF: 0.368 AC: 92063 AN: 250454 AF XY: 0.367

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.: 42 AF XY: 0.367 AC XY: 266775 AN XY: 726928

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

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

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of iodide peroxidase (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.18
DANN	Benign	0.35
PhyloP100		-5.1
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1126797; hg19: chr2-1497803; COSMIC: COSV61102057;