17-3573871-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_080704.4(TRPV1):c.1865G>A(p.Arg622Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,610,874 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (1 hom., cov: 30)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.105

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.050412744).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.1865G>A	p.Arg622Lys	missense_variant	14/17	ENST00000572705.2
TRPV1	NM_018727.5	c.1865G>A	p.Arg622Lys	missense_variant	13/16
TRPV1	NM_080705.4	c.1865G>A	p.Arg622Lys	missense_variant	13/16
TRPV1	NM_080706.3	c.1865G>A	p.Arg622Lys	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.1865G>A	p.Arg622Lys	missense_variant	14/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151766 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000376 AC: 9 AN: 239472 Hom.: 0 AF XY: 0.0000610 AC XY: 8 AN XY: 131118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000989

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000563

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1458992 Hom.: 0 Cov.: 33 AF XY: 0.0000289 AC XY: 21 AN XY: 725748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151882 Hom.: 1 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000498 AC: 6

EpiCase AF: 0.00

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

Apr 19, 2023

The c.1865G>A (p.R622K) alteration is located in exon 12 (coding exon 12) of the TRPV1 gene. This alteration results from a G to A substitution at nucleotide position 1865, causing the arginine (R) at amino acid position 622 to be replaced by a lysine (K). 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	0.071
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	8.2
Dann	Benign	0.93
DEOGEN2	Uncertain	0.57	D;D;D;D;.;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.045	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.050	T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.090	N;N;N;N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.26	N;.;.;N;N;.;N
REVEL	Uncertain	0.45
Sift	Benign	0.76	T;.;.;T;T;.;T
Sift4G	Benign	0.82	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.;B
Vest4		0.15
MutPred		0.34		.;.;.;.;Gain of methylation at R633 (P = 0.0073);.;.;
MVP		0.40
MPC		0.064
ClinPred		0.021	T
GERP RS		1.9
Varity_R		0.083
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781487428; hg19: chr17-3477165; COSMIC: COSV105848971; COSMIC: COSV105848971;