2-1496127-C-T

Variant names:

• chr2-1496127-C-T
• rs732608
• NM_001206744.2:c.2145C>T

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.2145C>T​(p.Pro715Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,612,706 control chromosomes in the GnomAD database, including 136,110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P715P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.42 (13520 hom., cov: 33)
  • Exomes 𝑓: 0.41 (122590 hom.)
• Consequence: TPO NM_001206744.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.72
• Publications: 27 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=0.139).
• BP6: Variant 2-1496127-C-T is Benign according to our data. Variant chr2-1496127-C-T is described in ClinVar as Benign. ClinVar VariationId is 256610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.481 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.2145C>T	p.Pro715Pro	synonymous	Exon 12 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.2145C>T	p.Pro715Pro	synonymous	Exon 12 of 17	NP_000538.3
	TPO	NM_175721.3		c.2145C>T	p.Pro715Pro	synonymous	Exon 11 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.2145C>T	p.Pro715Pro	synonymous	Exon 12 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.2145C>T	p.Pro715Pro	synonymous	Exon 12 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.1974C>T	p.Pro658Pro	synonymous	Exon 11 of 16	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63965 AN: 151950 Hom.: 13505 Cov.: 33

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.418

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.426

GnomAD2 exomes AF: 0.415 AC: 103605 AN: 249478 AF XY: 0.416

Gnomad AFR exome AF: 0.435

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.410

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.404

GnomAD4 exome AF: 0.408 AC: 595673 AN: 1460638 Hom.: 122590 Cov.: 74 AF XY: 0.410 AC XY: 297931 AN XY: 726516

African (AFR) AF: 0.450 AC: 15068 AN: 33470

American (AMR) AF: 0.439 AC: 19551 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9577 AN: 26110

East Asian (EAS) AF: 0.451 AC: 17875 AN: 39648

South Asian (SAS) AF: 0.500 AC: 43020 AN: 86078

European-Finnish (FIN) AF: 0.412 AC: 21967 AN: 53318

Middle Eastern (MID) AF: 0.375 AC: 2155 AN: 5746

European-Non Finnish (NFE) AF: 0.397 AC: 441353 AN: 1111376

Other (OTH) AF: 0.416 AC: 25107 AN: 60332

GnomAD4 genome AF: 0.421 AC: 64026 AN: 152068 Hom.: 13520 Cov.: 33 AF XY: 0.424 AC XY: 31487 AN XY: 74344

African (AFR) AF: 0.443 AC: 18375 AN: 41468

American (AMR) AF: 0.458 AC: 7002 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1299 AN: 3470

East Asian (EAS) AF: 0.418 AC: 2154 AN: 5148

South Asian (SAS) AF: 0.497 AC: 2392 AN: 4810

European-Finnish (FIN) AF: 0.420 AC: 4456 AN: 10600

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26982 AN: 67974

Other (OTH) AF: 0.424 AC: 894 AN: 2110

Alfa AF: 0.387 Hom.: 7964

Bravo AF: 0.420

Asia WGS AF: 0.457 AC: 1589 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Deficiency of iodide peroxidase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.4
DANN	Benign	0.48
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs732608; hg19: chr2-1499899; COSMIC: COSV61099918;