12-11061613-A-T

Variant names:

• chr12-11061613-A-T
• rs2708380
• NM_176887.2:c.682T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• Publications: 28 publications found

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]

ENSG00000275778 (HGNC:):

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]

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]

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]

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176887.2. 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
	TAS2R46	NM_176887.2	MANE Select	c.682T>A	p.Leu228Met	missense	Exon 1 of 1	NP_795368.2
	PRH1	NM_001291315.2		c.-133-14425T>A		intron	N/A	NP_001278244.1
	PRH1	NM_001291314.2		c.-294-14425T>A		intron	N/A	NP_001278243.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R46	ENST00000533467.1	TSL:6 MANE Select	c.682T>A	p.Leu228Met	missense	Exon 1 of 1	ENSP00000436450.1
	ENSG00000275778	ENST00000536668.2	TSL:5	n.-164-14425T>A		intron	N/A	ENSP00000482961.1
	PRR4	ENST00000535024.7	TSL:5	c.-133-14425T>A		intron	N/A	ENSP00000481571.3

Frequencies

GnomAD3 genomes AF: 0.378 AC: 55845 AN: 147564 Hom.: 6720 Cov.: 34

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

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.: 92 AF XY: 0.466 AC XY: 336896 AN XY: 722636

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

GnomAD4 genome AF: 0.378 AC: 55859 AN: 147686 Hom.: 6718 Cov.: 34 AF XY: 0.377 AC XY: 27193 AN XY: 72152

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: 72 AN: 284

European-Non Finnish (NFE) AF: 0.432 AC: 28336 AN: 65520

Other (OTH) AF: 0.356 AC: 733 AN: 2060

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.3
DANN	Benign	0.96
DEOGEN2	Benign	0.00068	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0019	N
MetaRNN	Benign	0.000082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PhyloP100		0.018
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.066
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Polyphen		0.88	P
Vest4		0.050
MPC		0.0036
ClinPred		0.013	T
GERP RS		-3.1
Varity_R		0.086
gMVP		0.035
Mutation Taster		=99/1	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: rs2708380; hg19: chr12-11214212; COSMIC: COSV67856878;