17-3591067-G-C

Variant names:

• chr17-3591067-G-C
• rs222748
• NM_080704.4:c.501C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_080704.4(TRPV1):​c.501C>G​(p.His167Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H167R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.727
• Publications: 24 publications found

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]

ENSG00000262304 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV1	NM_080704.4	c.501C>G	p.His167Gln	missense_variant	Exon 5 of 17	ENST00000572705.2	NP_542435.2
TRPV1	NM_018727.5	c.501C>G	p.His167Gln	missense_variant	Exon 4 of 16		NP_061197.4
TRPV1	NM_080705.4	c.501C>G	p.His167Gln	missense_variant	Exon 4 of 16		NP_542436.2
TRPV1	NM_080706.3	c.501C>G	p.His167Gln	missense_variant	Exon 3 of 15		NP_542437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV1	ENST00000572705.2	c.501C>G	p.His167Gln	missense_variant	Exon 5 of 17	1	NM_080704.4	ENSP00000459962.1
ENSG00000262304	ENST00000572919.1	n.*1785C>G		non_coding_transcript_exon_variant	Exon 10 of 14	5		ENSP00000461416.1
ENSG00000262304	ENST00000572919.1	n.*1785C>G		3_prime_UTR_variant	Exon 10 of 14	5		ENSP00000461416.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460564 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726434

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

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85972

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111454

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0556734), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1046

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.5
DANN	Benign	0.38
DEOGEN2	Benign	0.25	T;T;T;T;.;.;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.70	.;.;.;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.064	T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.12	N;N;N;N;.;.;.
PhyloP100		-0.73
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.9	N;.;.;N;N;.;N
REVEL	Uncertain	0.33
Sift	Benign	0.28	T;.;.;T;T;.;T
Sift4G	Benign	0.54	T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;.;B
Vest4		0.16
MutPred		0.37		Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);Loss of catalytic residue at D168 (P = 0.039);
MVP		0.19
MPC		0.065
ClinPred		0.43	T
GERP RS		-9.0
Varity_R		0.21
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs222748; hg19: chr17-3494361;