rs2069550

Variant names:

• chr8-132888141-T-C
• rs2069550
• NM_003235.5:c.2334T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-132888141-T-C
• chr8-132888141-T-A
• chr8-132888141-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003235.5(TG):​c.2334T>C​(p.Pro778Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,613,406 control chromosomes in the GnomAD database, including 241,744 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28101 hom., cov: 31)
  • Exomes 𝑓: 0.54 (213643 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -7.75
• Publications: 33 publications found

Genes affected

TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

TG Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 8-132888141-T-C is Benign according to our data. Variant chr8-132888141-T-C is described in ClinVar as Benign. ClinVar VariationId is 258989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.75 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003235.5. 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
	TG	NM_003235.5	MANE Select	c.2334T>C	p.Pro778Pro	synonymous	Exon 10 of 48	NP_003226.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TG	ENST00000220616.9	TSL:1 MANE Select	c.2334T>C	p.Pro778Pro	synonymous	Exon 10 of 48	ENSP00000220616.4	P01266-1

Frequencies

GnomAD3 genomes AF: 0.601 AC: 91302 AN: 151814 Hom.: 28063 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.598

Gnomad MID AF: 0.567

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.592

GnomAD2 exomes AF: 0.581 AC: 145393 AN: 250364 AF XY: 0.582

Gnomad AFR exome AF: 0.712

Gnomad AMR exome AF: 0.552

Gnomad ASJ exome AF: 0.608

Gnomad EAS exome AF: 0.763

Gnomad FIN exome AF: 0.582

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.576

GnomAD4 exome AF: 0.536 AC: 783891 AN: 1461474 Hom.: 213643 Cov.: 72 AF XY: 0.540 AC XY: 392394 AN XY: 727018

African (AFR) AF: 0.712 AC: 23846 AN: 33478

American (AMR) AF: 0.561 AC: 25043 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 15969 AN: 26134

East Asian (EAS) AF: 0.761 AC: 30208 AN: 39686

South Asian (SAS) AF: 0.651 AC: 56127 AN: 86234

European-Finnish (FIN) AF: 0.579 AC: 30909 AN: 53382

Middle Eastern (MID) AF: 0.604 AC: 3486 AN: 5768

European-Non Finnish (NFE) AF: 0.508 AC: 564498 AN: 1111754

Other (OTH) AF: 0.560 AC: 33805 AN: 60386

GnomAD4 genome AF: 0.602 AC: 91390 AN: 151932 Hom.: 28101 Cov.: 31 AF XY: 0.609 AC XY: 45189 AN XY: 74248

African (AFR) AF: 0.708 AC: 29338 AN: 41424

American (AMR) AF: 0.596 AC: 9096 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2143 AN: 3472

East Asian (EAS) AF: 0.764 AC: 3943 AN: 5164

South Asian (SAS) AF: 0.661 AC: 3181 AN: 4810

European-Finnish (FIN) AF: 0.598 AC: 6301 AN: 10530

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.522 AC: 35456 AN: 67958

Other (OTH) AF: 0.584 AC: 1231 AN: 2108

Alfa AF: 0.555 Hom.: 64484

Bravo AF: 0.605

Asia WGS AF: 0.678 AC: 2359 AN: 3478

EpiCase AF: 0.535

EpiControl AF: 0.535

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Iodotyrosyl coupling defect (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.0030
DANN	Benign	0.37
PhyloP100		-7.7
Mutation Taster		=76/24	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: rs2069550; hg19: chr8-133900386; COSMIC: COSV107275232; COSMIC: COSV107275232;