2-233942704-A-C

Position:

• chr2-233942704-A-C

Variant summary

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

The NM_024080.5(TRPM8):​c.655A>C​(p.Met219Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM8	NM_024080.5	c.655A>C	p.Met219Leu	missense_variant	6/26	ENST00000324695.9	NP_076985.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM8	ENST00000324695.9	c.655A>C	p.Met219Leu	missense_variant	6/26	1	NM_024080.5	ENSP00000323926	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jan 02, 2024

The c.655A>C (p.M219L) alteration is located in exon 6 (coding exon 5) of the TRPM8 gene. This alteration results from a A to C substitution at nucleotide position 655, causing the methionine (M) at amino acid position 219 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.42	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.66	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.50	T;T;D
Sift4G	Benign	0.067	T;T;T
Polyphen		0.84	P;.;.
Vest4		0.55
MutPred		0.45		Loss of sheet (P = 0.1501);.;.;
MVP		0.37
MPC		0.56
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.42

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-234851348;