12-11061613-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_176887.2(TAS2R46):c.682T>A(p.Leu228Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,599,916 control chromosomes in the GnomAD database, including 173,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.38 ( 6718 hom., cov: 34)

Exomes 𝑓: 0.47 ( 166939 hom. )

Consequence

TAS2R46
NM_176887.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0180

Publications

28 publications found

Variant links:

Genes affected

TAS2R46 (HGNC:18877): (taste 2 receptor member 46) TAS2R46 belongs to the large TAS2R receptor family. TAS2Rs are expressed on the surface of taste receptor cells and mediate the perception of bitterness through a G protein-coupled second messenger pathway (Conte et al., 2002 [PubMed 12584440]). For further information on TAS2Rs, see MIM 604791.[supplied by OMIM, Sep 2009]

TAS2R46 links:

ENSG00000275778 (HGNC:):

ENSG00000275778 links:

PRH1 (HGNC:9366): (proline rich protein HaeIII subfamily 1) This gene encodes a member of the heterogeneous family of proline-rich salivary glycoproteins. The encoded preproprotein undergoes proteolytic processing to generate one or more mature isoforms before secretion from the parotid and submandibular/sublingual glands. Multiple distinct alleles of this locus including the parotid isoelectric-focusing variant slow (PIF-s), the parotid acidic protein (Pa), and the double band slow (Db-s) isoforms have been characterized. The reference genome encodes the Db-s allele. Certain alleles of this gene are associated with susceptibility to dental caries. This gene is located in a cluster of closely related salivary proline-rich proteins on chromosome 12. Co-transcription of this gene with adjacent genes has been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

PRH1 links:

PRR4 (HGNC:18020): (proline rich 4) This gene encodes a member of the proline-rich protein family that lacks a conserved repetitive domain. This protein may play a role in protective functions in the eye. Alternative splicing result in multiple transcript variants. Read-through transcription also exists between this gene and the upstream PRH1 (proline-rich protein HaeIII subfamily 1) gene. [provided by RefSeq, Feb 2011]

PRR4 links:

TAS2R14 (HGNC:14920): (taste 2 receptor member 14) This gene product belongs to the family of candidate taste receptors that are members of the G-protein-coupled receptor superfamily. These proteins are specifically expressed in the taste receptor cells of the tongue and palate epithelia. They are organized in the genome in clusters and are genetically linked to loci that influence bitter perception in mice and humans. In functional expression studies, they respond to bitter tastants. This gene maps to the taste receptor gene cluster on chromosome 12p13. [provided by RefSeq, Jul 2008]

TAS2R14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.21798E-5).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TAS2R46	NM_176887.2 link	c.682T>A	p.Leu228Met	missense_variant	Exon 1 of 1	ENST00000533467.1	NP_795368.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TAS2R46	ENST00000533467.1 link	c.682T>A	p.Leu228Met	missense_variant	Exon 1 of 1	6	NM_176887.2	ENSP00000436450.1
ENSG00000275778	ENST00000536668.2 link	n.-164-14425T>A		intron_variant	Intron 1 of 9	5		ENSP00000482961.1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

55845

AN:

147564

Hom.:

6720

Cov.:

show subpopulations

Gnomad AFR

AF:

0.311

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.280

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.221

Gnomad FIN

AF:

0.498

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.432

Gnomad OTH

AF:

0.359

GnomAD2 exomes

AF:

0.429

AC:

107807

AN:

251256

AF XY:

0.421

show subpopulations

Gnomad AFR exome

AF:

0.357

Gnomad AMR exome

AF:

0.433

Gnomad ASJ exome

AF:

0.318

Gnomad EAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.594

Gnomad NFE exome

AF:

0.501

Gnomad OTH exome

AF:

0.437

GnomAD4 exome

AF:

0.473

AC:

687408

AN:

1452230

Hom.:

166939

Cov.:

AF XY:

0.466

AC XY:

336896

AN XY:

722636

show subpopulations

African (AFR)

AF:

0.346

AC:

11526

AN:

33346

American (AMR)

AF:

0.429

AC:

19028

AN:

44386

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

8064

AN:

26026

East Asian (EAS)

AF:

0.222

AC:

8802

AN:

39600

South Asian (SAS)

AF:

0.246

AC:

21174

AN:

86044

European-Finnish (FIN)

AF:

0.591

AC:

31188

AN:

52814

Middle Eastern (MID)

AF:

0.286

AC:

1645

AN:

5754

European-Non Finnish (NFE)

AF:

0.507

AC:

559754

AN:

1104266

Other (OTH)

AF:

0.437

AC:

26227

AN:

59994

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

24302

48604

72907

97209

121511

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16118

32236

48354

64472

80590

<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:

0.378

AC:

55859

AN:

147686

Hom.:

6718

Cov.:

AF XY:

0.377

AC XY:

27193

AN XY:

72152

show subpopulations

African (AFR)

AF:

0.311

AC:

12661

AN:

40740

American (AMR)

AF:

0.374

AC:

5557

AN:

14848

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

960

AN:

3428

East Asian (EAS)

AF:

0.204

AC:

1042

AN:

5112

South Asian (SAS)

AF:

0.220

AC:

1055

AN:

4786

European-Finnish (FIN)

AF:

0.498

AC:

5006

AN:

10048

Middle Eastern (MID)

AF:

0.254

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.432

AC:

28336

AN:

65520

Other (OTH)

AF:

0.356

AC:

733

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

1654

3308

4961

6615

8269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.423

Hom.:

3731

TwinsUK

AF:

0.516

AC:

1914

ALSPAC

AF:

0.521

AC:

2007

ESP6500AA

AF:

0.367

AC:

1615

ESP6500EA

AF:

0.488

AC:

4198

ExAC

AF:

0.425

AC:

51662

Asia WGS

AF:

0.285

AC:

994

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.3

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.00068

Eigen

Benign

-0.78

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0019

MetaRNN

Benign

0.000082

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

PhyloP100

0.018

PrimateAI

Benign

0.30

PROVEAN

Benign

0.040

REVEL

Benign

0.066

Sift

Benign

0.23

Sift4G

Benign

0.29

Polyphen

0.88

Vest4

0.050

MPC

0.0036

ClinPred

0.013

GERP RS

-3.1

Varity_R

0.086

gMVP

0.035

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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

Computational scores

Splicing

Publications

Other links and lift over