12-11061613-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

PRH1-TAS2R14 (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]

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TAS2R46	NM_176887.2	c.682T>A	p.Leu228Met	missense_variant	1/1	ENST00000533467.1
PRH1-TAS2R14	NM_001316893.2	c.-133-14425T>A		intron_variant
PRH1-PRR4	NR_037918.2	n.205-14425T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TAS2R46	ENST00000533467.1	c.682T>A	p.Leu228Met	missense_variant	1/1		NM_176887.2	P1
TAS2R14	ENST00000381852.4	n.153-14425T>A		intron_variant, non_coding_transcript_variant		2
PRH1	ENST00000541977.5	n.124-14425T>A		intron_variant, non_coding_transcript_variant		2
PRH1	ENST00000546265.1	n.359-14425T>A		intron_variant, non_coding_transcript_variant		5

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

GnomAD3 exomes AF: 0.429 AC: 107807 AN: 251256 Hom.: 24929 AF XY: 0.421 AC XY: 57231 AN XY: 135810

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 SAS exome AF: 0.247

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

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.222

Gnomad4 SAS exome AF: 0.246

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.507

Gnomad4 OTH exome AF: 0.437

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

Gnomad4 AFR AF: 0.311

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.498

Gnomad4 NFE AF: 0.432

Gnomad4 OTH AF: 0.356

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	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
MutationTaster	Benign	1.0	P
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

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

LitVar

Other links and lift over

dbSNP: rs2708380; hg19: chr12-11214212; COSMIC: COSV67856878;