17-3566826-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_080704.4(TRPV1):c.2509G>A(p.Gly837Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.779

Genes affected

TRPV1 (HGNC:12716): (transient receptor potential cation channel subfamily V member 1) Capsaicin, the main pungent ingredient in hot chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The protein encoded by this gene is a receptor for capsaicin and is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. This receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo. Four transcript variants encoding the same protein, but with different 5' UTR sequence, have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10764256).
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.2509G>A	p.Gly837Arg	missense_variant	17/17	ENST00000572705.2
TRPV1	NM_018727.5	c.2509G>A	p.Gly837Arg	missense_variant	16/16
TRPV1	NM_080705.4	c.2509G>A	p.Gly837Arg	missense_variant	16/16
TRPV1	NM_080706.3	c.2509G>A	p.Gly837Arg	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.2509G>A	p.Gly837Arg	missense_variant	17/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000803 AC: 20 AN: 249042 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135126

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000424 AC: 62 AN: 1461442 Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25 AN XY: 727020

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000744 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The c.2509G>A (p.G837R) alteration is located in exon 15 (coding exon 15) of the TRPV1 gene. This alteration results from a G to A substitution at nucleotide position 2509, causing the glycine (G) at amino acid position 837 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.34	T;T;T;T;.;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.1	L;L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.8	N;.;.;N;N;.;N
REVEL	Benign	0.26
Sift	Benign	0.049	D;.;.;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		0.033	B;B;B;B;B;.;B
Vest4		0.095
MutPred		0.13		.;.;.;.;Loss of ubiquitination at K850 (P = 0.0118);.;.;
MVP		0.72
MPC		0.078
ClinPred		0.035	T
GERP RS		3.8
Varity_R		0.063
gMVP		0.27

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: rs201622414; hg19: chr17-3470120; COSMIC: COSV51520865;