2-233939143-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024080.5(TRPM8):c.494T>C(p.Phe165Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.76

Genes affected

TRPM8 (HGNC:17961): (transient receptor potential cation channel subfamily M member 8) Predicted to enable ligand-gated calcium channel activity. Predicted to be involved in calcium ion transmembrane transport and positive regulation of cold-induced thermogenesis. Predicted to act upstream of or within several processes, including cellular calcium ion homeostasis; response to cold; and thermoception. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM8	NM_024080.5	c.494T>C	p.Phe165Ser	missense_variant	5/26	ENST00000324695.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM8	ENST00000324695.9	c.494T>C	p.Phe165Ser	missense_variant	5/26	1	NM_024080.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250606 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Dec 22, 2023

The c.494T>C (p.F165S) alteration is located in exon 5 (coding exon 4) of the TRPM8 gene. This alteration results from a T to C substitution at nucleotide position 494, causing the phenylalanine (F) at amino acid position 165 to be replaced by a serine (S). 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	0.82
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		0.18	B;.;.
Vest4		0.91
MutPred		0.72		Gain of disorder (P = 0.0168);.;.;
MVP		0.43
MPC		0.45
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.82

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: rs201611229; hg19: chr2-234847787;