chr2-233926608-T-A

Position:

• chr2-233926608-T-A

Variant summary

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

The NM_024080.5(TRPM8):​c.71T>A​(p.Leu24Gln) 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: 32)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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.71T>A	p.Leu24Gln	missense_variant	2/26	ENST00000324695.9	NP_076985.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM8	ENST00000324695.9	c.71T>A	p.Leu24Gln	missense_variant	2/26	1	NM_024080.5	ENSP00000323926	P1
TRPM8	ENST00000444298.5	c.71T>A	p.Leu24Gln	missense_variant, NMD_transcript_variant	2/25	1		ENSP00000396745
TRPM8	ENST00000433712.6	c.-653T>A		5_prime_UTR_variant	2/24	5		ENSP00000404423

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Apr 20, 2023

The c.71T>A (p.L24Q) alteration is located in exon 2 (coding exon 1) of the TRPM8 gene. This alteration results from a T to A substitution at nucleotide position 71, causing the leucine (L) at amino acid position 24 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.30		Loss of sheet (P = 0.0084);
MVP		0.87
MPC		0.68
ClinPred		0.95	D
GERP RS		5.0
Varity_R		0.36
gMVP		0.66

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: chr2-234835253;