17-3573890-A-G

Variant summary

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

The NM_080704.4(TRPV1):c.1846T>C(p.Trp616Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,611,310 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223

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=0.05562979).
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.1846T>C	p.Trp616Arg	missense_variant	14/17	ENST00000572705.2
TRPV1	NM_018727.5	c.1846T>C	p.Trp616Arg	missense_variant	13/16
TRPV1	NM_080705.4	c.1846T>C	p.Trp616Arg	missense_variant	13/16
TRPV1	NM_080706.3	c.1846T>C	p.Trp616Arg	missense_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.1846T>C	p.Trp616Arg	missense_variant	14/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151748 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000282 AC: 69 AN: 244618 Hom.: 0 AF XY: 0.000263 AC XY: 35 AN XY: 133328

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000543

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000605 AC: 883 AN: 1459562 Hom.: 1 Cov.: 33 AF XY: 0.000605 AC XY: 439 AN XY: 726186

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.000763

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151748 Hom.: 0 Cov.: 30 AF XY: 0.000418 AC XY: 31 AN XY: 74086

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.000218

EpiControl AF: 0.000534

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

May 11, 2022

The c.1846T>C (p.W616R) alteration is located in exon 12 (coding exon 12) of the TRPV1 gene. This alteration results from a T to C substitution at nucleotide position 1846, causing the tryptophan (W) at amino acid position 616 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	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	14
Dann	Benign	0.83
DEOGEN2	Uncertain	0.63	D;D;D;D;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.097	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.056	T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.69	N;N;N;N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;.;.;N;N;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.37	T;.;.;T;T;.;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.;B
Vest4		0.17
MVP		0.36
MPC		0.11
ClinPred		0.017	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
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: rs200601093; hg19: chr17-3477184;