chr12-11061546-C-T

Variant names:

• chr12-11061546-C-T
• rs2708381
• NM_176887.2:c.749G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_176887.2(TAS2R46):​c.749G>A​(p.Trp250*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,606,394 control chromosomes in the GnomAD database, including 32,709 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (398 hom., cov: 37)
  • Exomes 𝑓: 0.23 (32311 hom.)
• Consequence: TAS2R46 NM_176887.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.445
• Publications: 43 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 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.749G>A	p.Trp250*	stop_gained	Exon 1 of 1	NP_795368.2	P59540
	PRH1	NM_001291315.2		c.-133-14358G>A		intron	N/A	NP_001278244.1
	PRH1	NM_001291314.2		c.-294-14358G>A		intron	N/A	NP_001278243.1	A0A087WV42

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R46	ENST00000533467.1	TSL:6 MANE Select	c.749G>A	p.Trp250*	stop_gained	Exon 1 of 1	ENSP00000436450.1	P59540
	ENSG00000275778	ENST00000536668.2	TSL:5	n.-164-14358G>A		intron	N/A	ENSP00000482961.1	A0A087WZY1
	PRR4	ENST00000535024.7	TSL:5	c.-133-14358G>A		intron	N/A	ENSP00000481571.3	A0A087WY73

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30776 AN: 151568 Hom.: 398 Cov.: 37

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.228 AC: 57076 AN: 250882 AF XY: 0.225

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.211

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.216

GnomAD4 exome AF: 0.228 AC: 330957 AN: 1454708 Hom.: 32311 Cov.: 80 AF XY: 0.226 AC XY: 163261 AN XY: 723716

African (AFR) AF: 0.213 AC: 7089 AN: 33308

American (AMR) AF: 0.228 AC: 10114 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4194 AN: 26030

East Asian (EAS) AF: 0.212 AC: 8367 AN: 39492

South Asian (SAS) AF: 0.180 AC: 15459 AN: 85910

European-Finnish (FIN) AF: 0.259 AC: 13715 AN: 53040

Middle Eastern (MID) AF: 0.163 AC: 941 AN: 5758

European-Non Finnish (NFE) AF: 0.233 AC: 257919 AN: 1106640

Other (OTH) AF: 0.219 AC: 13159 AN: 60078

GnomAD4 genome AF: 0.203 AC: 30784 AN: 151686 Hom.: 398 Cov.: 37 AF XY: 0.204 AC XY: 15168 AN XY: 74180

African (AFR) AF: 0.196 AC: 8097 AN: 41402

American (AMR) AF: 0.197 AC: 2998 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 521 AN: 3460

East Asian (EAS) AF: 0.194 AC: 999 AN: 5154

South Asian (SAS) AF: 0.169 AC: 813 AN: 4806

European-Finnish (FIN) AF: 0.238 AC: 2512 AN: 10552

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14276 AN: 67766

Other (OTH) AF: 0.194 AC: 410 AN: 2112

Alfa AF: 0.219 Hom.: 4490

TwinsUK AF: 0.236 AC: 875

ALSPAC AF: 0.249 AC: 958

ESP6500AA AF: 0.229 AC: 1007

ESP6500EA AF: 0.227 AC: 1953

ExAC AF: 0.226 AC: 27438

Asia WGS AF: 0.235 AC: 818 AN: 3478

EpiCase AF: 0.223

EpiControl AF: 0.225

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	31
DANN	Benign	0.73
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.015	N
PhyloP100		-0.45
Vest4		0.030
GERP RS		-0.023
Mutation Taster		=191/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs2708381; hg19: chr12-11214145; COSMIC: COSV99061941;