chr12-11022255-C-T

Variant names:

• chr12-11022255-C-T
• rs12578654
• NM_176888.2:c.317G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_176888.2(TAS2R19):​c.317G>A​(p.Cys106Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.015 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TAS2R19 NM_176888.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.746
• Publications: 2 publications found

Genes affected

TAS2R19 (HGNC:19108): (taste 2 receptor member 19) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway and sensory perception of taste. Is integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008672774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176888.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R19	NM_176888.2	MANE Select	c.317G>A	p.Cys106Tyr	missense	Exon 1 of 1	NP_795369.1
	PRH1	NM_001291315.2		c.36+24765G>A		intron	N/A	NP_001278244.1
	PRH1	NM_001291314.2		c.-126+24765G>A		intron	N/A	NP_001278243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TAS2R19	ENST00000390673.2	TSL:6 MANE Select	c.317G>A	p.Cys106Tyr	missense	Exon 1 of 1	ENSP00000375091.2
	ENSG00000275778	ENST00000536668.2	TSL:5	n.109+12527G>A		intron	N/A	ENSP00000482961.1
	PRH1	ENST00000703543.1		c.-126+24765G>A		intron	N/A	ENSP00000515364.1

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 1421 AN: 93532 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00575

Gnomad AMI AF: 0.0182

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251022 AF XY: 0.00

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461502 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 727048

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111742

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0152 AC: 1423 AN: 93674 Hom.: 0 Cov.: 33 AF XY: 0.0162 AC XY: 743 AN XY: 45954

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00573 AC: 182 AN: 31774

American (AMR) AF: 0.0229 AC: 200 AN: 8750

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 32 AN: 1912

East Asian (EAS) AF: 0.0352 AC: 92 AN: 2616

South Asian (SAS) AF: 0.0254 AC: 66 AN: 2596

European-Finnish (FIN) AF: 0.0224 AC: 137 AN: 6120

Middle Eastern (MID) AF: 0.0352 AC: 5 AN: 142

European-Non Finnish (NFE) AF: 0.0176 AC: 669 AN: 38002

Other (OTH) AF: 0.0244 AC: 31 AN: 1268

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0479 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.23
DANN	Benign	0.41
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0020	N
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-3.4	N
PhyloP100		0.75
PrimateAI	Benign	0.42	T
PROVEAN	Benign	8.7	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.63		Loss of catalytic residue at L107 (P = 0.0317)
MVP		0.14
MPC		0.0075
ClinPred		0.021	T
GERP RS		1.3
PromoterAI		-0.010	Neutral
Varity_R		0.039
gMVP		0.28
Mutation Taster		=100/0	polymorphism

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: rs12578654; hg19: chr12-11174854;