17-3573719-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_080704.4(TRPV1):c.2017A>C(p.Ile673Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.78

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.2017A>C	p.Ile673Leu	missense_variant	14/17	ENST00000572705.2
TRPV1	NM_018727.5	c.2017A>C	p.Ile673Leu	missense_variant	13/16
TRPV1	NM_080705.4	c.2017A>C	p.Ile673Leu	missense_variant	13/16
TRPV1	NM_080706.3	c.2017A>C	p.Ile673Leu	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.2017A>C	p.Ile673Leu	missense_variant	14/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461862 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jun 30, 2022

The c.2017A>C (p.I673L) alteration is located in exon 12 (coding exon 12) of the TRPV1 gene. This alteration results from a A to C substitution at nucleotide position 2017, causing the isoleucine (I) at amino acid position 673 to be replaced by a leucine (L). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;D;D;D;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.0	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.9	N;.;.;N;N;.;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D;.;.;D;D;.;D
Sift4G	Uncertain	0.022	D;D;D;D;D;D;D
Polyphen		0.73	P;P;P;P;P;.;B
Vest4		0.71
MutPred		0.42		.;.;.;.;Loss of catalytic residue at I684 (P = 0.4202);.;.;
MVP		0.47
MPC		0.078
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.74

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: rs2074891314; hg19: chr17-3477013;