NM_024080.5:c.1256G>C

Variant names:

• chr2-233955144-G-C
• rs7593557
• NM_024080.5:c.1256G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024080.5(TRPM8):​c.1256G>C​(p.Ser419Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPM8 NM_024080.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• Publications: 26 publications found

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]

ENSG00000237581 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10344082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024080.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM8	NM_024080.5	MANE Select	c.1256G>C	p.Ser419Thr	missense	Exon 11 of 26	NP_076985.4
	TRPM8	NM_001397606.1		c.1256G>C	p.Ser419Thr	missense	Exon 11 of 22	NP_001384535.1
	TRPM8	NM_001397607.1		c.1106G>C	p.Ser369Thr	missense	Exon 10 of 25	NP_001384536.1	A0A1L1Z857

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPM8	ENST00000324695.9	TSL:1 MANE Select	c.1256G>C	p.Ser419Thr	missense	Exon 11 of 26	ENSP00000323926.4	Q7Z2W7-1
	TRPM8	ENST00000444298.5	TSL:1	n.*535G>C		non_coding_transcript_exon	Exon 12 of 25	ENSP00000396745.1	F8WD55
	TRPM8	ENST00000444298.5	TSL:1	n.*535G>C		3_prime_UTR	Exon 12 of 25	ENSP00000396745.1	F8WD55

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.066
Sift	Benign	0.035	D
Sift4G	Uncertain	0.048	D
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.24		Gain of relative solvent accessibility (P = 0.0507)
MVP		0.34
MPC		0.15
ClinPred		0.22	T
GERP RS		6.0
Varity_R		0.061
gMVP		0.23
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs7593557; hg19: chr2-234863788;